Process for the preparation of 9beta,10alpha-steroids



United States Patent US. Cl. 260-397.4 18 Claims ABSTRACT OF THEDISCLOSURE This invention is directed to processes for the preparationof 9/3,10a-steroids of the pregnane and androstane series. Steroid endproducts prepared in accordance with the processes of this invention arepharmacologically useful as anabolic, anti-androgenic, progestationaland salt-retaining agents.

RELATED APPLICATIONS This application is a division of applicantscopending application Ser. No. 499,094, filed Oct. 20, 1965, entitledIntermediates and Processes, which is a continuationin-part ofapplicants copending application Ser. No. 400,206, filed Sept. 29, 1964,entitled Intermediates and Processes.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novelchemical intermediates and processes useful in the preparation ofsteroids. Natural steroids possess a 9a-10B-stereochemicalconfiguration. Steroidal compounds possessing the unnatural95,10oz-configuration represent a pharmaceutically valuable class ofcompounds which, even though numerous members are known in the art,cannot be obtained by totally classical chemical means. In fact, theonly known methods for obtaining steroids possessing the unnatural9,8,l0a-configuration involve at least one photochemical reaction. Suchphotochemical reactions involve irradiation with ultraviolet light ofstrong intensity for long periods of time and, in comparison with purelychemical reactions, are very inefiicient and give only small yields.

It is an object of the present invention to provide intermediates andprocesses which enable the preparation of 9;3,10a-steroids Without thenecessity of proceeding through a photochemical reaction. It is also anobject of this invention to provide novel intermediates and processeswhich will enable the further exploration of steroids having theunnatural 9,6,10a-configuration. It is also an object of this inventionto provide novel 9,6,l0a-steroids.

The novel intermediates and processes of this invention are valuable andprovide a new synthetic route completely of a classical chemical nature,i.e. involving no photochemical reaction, for converting steroids havingthe normal configuration into steroidal compounds possessing theunnatural 9,B,10a-configuration.

In one aspect, the novel intermediates and processes of this inventionenable the preparation of 9B,l0u-steroids of the androstane series ofthe formula 3,496,199 Patented Feb. 17, 1970 wherein R is, individually,selected from the group consisting of hydroxy and lower alkanoyloxy; Ris, individually, hydrogen or lower alkyl and R and R taken together,are selected from the group consisting of (17;?- OH, l7u-lower-alkanoicacid lactone) and 0x0; R is selected from the group consisting ofhydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected fromthe group consisting of hydrogen and lower alkyl and X is a substituentin the 6- or 7-position selected from the group consisting of hydrogen,lower alkyl, lower alkyl thio, lower alkanoylthio and halogen. Compoundsof Formula I are useful as anabolic agents.

Other 9,B,l0a-androstanes, the preparation of which is enabled by theintermediates and processes of this invention, are of the formulae R1HHCI 1 1k 1 "-owera eny H39 H (\i/N/a H I H o R1 H3O I --l0wer alkynylwvR Hap H E/ t l P 0 Y (III) wherein R R Y and X have the same meaningas above. Compounds of Formula III are useful as progestational agentsand compounds of Formula II are useful as anti-androgenic agents.

In another embodiment of this invention, the novel compounds andintermediates provided by this invention enable the preparation of9,6,1000-St6f0id8 of the -pregnane series of the formula wherein Y and Xhave the same meaning as above; R is selected from the group consistingof hydrogen, lower alkyl, fluoro, hydroxy and lower alkanoyloxy; R isselected from the group consisting of hydrogen and halogen; and R isselected from the group consisting of hydrogen, lower alkyl, hydroxy andhalogen. Compounds of Formula IV are useful as progestational agents.

Other 9fl,l0a-steroids of the 17;S'-pregnane series, preparable from thenovel compounds and process of this invention, are of the formula CHzOEwherein R R Y and X have the same meaning as above. Compounds of FormulaV are useful as salt-retaining agents, i.e. are useful in the treatmentof Addisons disease.

As used herein, the term lower alkyl comprehends both straight andbranched chain saturated hydrocarbon groups, such as methyl, ethyl,propyl, isopropyl and the like. Similarly, the term lower alkanoylcomprehends groups such as acetyl and the like, and the term loweralkanoyloxy comprehends groups e.g. formyloxy acetoxy and the like. Inthe same manner, the term lower alkenyl comprehends groups such as vinyland the like, and the term lower alkynyl comprehends groups such asethinyl and the like. Halogen comprehends all four halogens, i.e.iodine, bromine, chlorine and fluorine.

The expression (1718-011, 17a-lower alkanoic acid lactone) refers to aconfiguration on the C-17 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g. polymethylenes such as ethylene,propylene or the like.

With respect to substituents in the 6- and 7-position, preferredcompounds are those having hydrogen or lower alkyl in 6- or 7-position,and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of9;3,l0a-androstanes of Formulae I-III and of 9;3,l0a-17,B-pregnanes ofFormulae IV-V which comprises the hydrogenation ofdesA-androst-9-en-5-ones or of desA-l7fi-pregn-9-en-5-ones to95,10B-desA-androstan-S-ones or 919,1Ofl-desA-l7g8-pregnan-5-ones,respectively, followed by condensation with a lower alkyl vinyl ketonewith methyl or ethyl vinyl ketone preferred (as well as substitutestherefor such as l-tertiary amino- 3-butanone, l-tertiaryamino-3-pentanone and quaternary ammonium salts thereof),l-Q-butan-3-one, 1-Q-butan-3- one lower alkylene ketal, l-Q-butan-3-ol,esterified l-Q- butan-3-ol, 1-Q-butan3-ol ether, 1,3-dichlorobut-2-ene,1,3-dichloropent-2-ene, l-pentan-3-one, l-Qpentan-3-one lower alkyleneketal, 1-Q-pentan-3-ol, esterified 1-Q- pentan-3-ol or l-Q-pentan-3-olether, which condensation yields the desired 9,6,10a-steroids. Thesymbol Q is bromine, chlorine or iodine, with the former two beingpreferred. This invention also provides a number of different methodsfor the preparation of said desA-androst- 9-en-5-one ordesA-l7/3-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst-4- ene or3-oxo-17fi-pregn-4-ene series is subjected to an oxidative ring openingof the A-ring yielding a 5-oxo-3,5- seco-A-norandrostan-3-oic acid or a5-oxo-3 .S-seco-A-norl7 8-pregnan-3-oic acid, which 3-oic acid can thenbe converted to a mixture of a l0a-desA-androstan-5-one and aIOfi-desA-androstan-S-one or a mixture of a llla-desA-l7fi-pregnan-5-one and a lOfi-desA-17(3-pregnan-5-one.

The conversion of the 3-oic acid to the desA-compound can be effectedeither by pyrolysis of a salt of said 3-oic acid or via the enollactone, ie a 4-oxoandrost-5-en-3- one or a 4-oxo-175-pregn-5-en-3-one,which upon reaction with a Grignard reagent gives an aldol, which inturn can be converted into the desired desA-compound. The desA- compoundcan then be converted into the starting material desA-androst9-en-S-oneor desA-17fi-pregn-9-en-5- one via a two-step sequence of halogenationand dehydrohalogenation.

In another embodiment of this invention, desA-androst- 9-en-5-one ordesA-17B-pregn-9-en-5-one starting materials can be prepared fromll-hydroxy steroids of the 3- oxo-androst-4-ene or3-oxo-l7fi-pregn-4-ene series. This can be effected in a variety ofways. In one approach, an ll-hydroxy group of a steroid of the3-oxo-androst-4-ene or 3-0Xo-l7B-pregn-4-ene series is converted into aleaving group, for example, a sulfonic acid ester or carboxylic acidester. Oxidative ring opening of the A-ring of the thus formedll-(esterified hydroxy)-containing compound yields the correspondingll-(esterified hydroxy)-5-oxo- 3,5-seco-A-norandrostan-3-oic acid orll-(esterified hydroxy) 5 oxo 3,5 seco A nor 17d pregnan 3 oic acidwhich upon pyrolysis of a salt of said 3-oic acid yields the desireddesA-androst-9-en-5-one or desA-17B- pregn-9-en-5-one starting material.

A further approach involves formation of an ll-hydroxy-desA-androstan 5one or ll-hydroxy-desA- 17 3- pregnan-S-one from an ll-hydroxy steroidof the 3-ox0- androst-4-ene or 3-oxo-17/3-pregn-4-ene series via anoxidative ring opening of the A-ring of said ll-hydroxy steroid whichyields an ll-hydroxy-5-oxo-A-nor-3,S-secoandrostan-B-oic acid3,11-lactone or an ll-hydroxy-S-oxo- 3,5-seco-17 8pregnan-3-oic acid3,1l-lactone which, in turn is converted into a salt of thecorresponding keto acid which salt upon pyrolysis gives thell-hydroxy-desA- androst-an-S-one or 1l-hydroxy-desA-l7B-pregnan-5-one.Esterification of the ll-hydroxy moiety of the so-obtained compound withan acid moiety yields an ll-(esterified hydroxy)-desA-androstan-5-one oran 11 (esterified hydroxy)-desA-l7fi-pregnan-5-one which uponelimination of the leaving group (i.e., the esterified hydroxy moiety)gives the desired desA-androst-Q-en-S-one or desA-l7flpregn-9-en-5-onestarting material. Though, in the above reaction sequence either lloc-OHor llfi-OH starting material steroids can be used, it is preferred touse Ila-OH starting materials.

As will be appreciated from the above discussion, neither the specificreaction steps nor the reaction sequences of this invention involve anymodification of substituents found in the 16- and/or l7-position of thestart ing material natural steroids. However, in order to obtainunnatural 9B,10m-steroids of Formulas LV, it is necessary or desirableto protect certain of the 16- and/or 17-substituents against one or moreof the reaction steps involved. It is also convenient to initiallyprotect such a substituent in the starting material natural steroid andmaintain the substituent in its protected forrn throughout the entirereaction sequence, regenerating the desired substituent only when thesteroid of Formulas I-V possessing the unnatural 9fi,l0a-configurationis obtained. On the other hand, it is sometimes convenient to insert aprotecting group only before a certain reaction step or se quence ofreaction steps. Said protecting group can then be maintained until thefinal reaction step or can be split Off at some intermediate stage. Theprotecting groups can be inserted and split oil by means known per se.The desirability of having protecting groups present will be furtherdiscussed below when the specific reaction steps are discussed indetail. The various substituents which are susceptible to beingprotected are exemplified by the 16-hydroxy group in a compound of anyof Formulas I-V, the l7fi-hydroxy group in a compound of any of FormulasI-III, the l7a-hydroxy or ZO-oxo group in a compound of any of FormulasIV-V, the 21-hydroxy group of a compound of Formula V or the 17-oxogroup of a compound of Formula I.

The l7-oxo or *oxo group is suitably protected by ketalization, i.e., byreaction with a lower alkanediol, to yield a l7-lower alkylene dioxy or20-lower alkylene dioxy compound, i.e., a 17-ketal or a ZO-ketal.

The l6-hydroxy, l7oc-hYdr0XY, 17fi-hydroxy or 21-hydroxy moieties can beprotected by esterification and/or etherification of the hydroxy group.Any available acid which will form an ester that can subsequently behydrolyzed to regenerate the hydroxy group is suitable. Exemplary acidsuseful for this purpose are lower alkanoic acids, e.g. acetic acid,caproic acid, benzoic acid, phosphoric acid and lower alkanedicarboxylic acids, e.g. succinic acid. Also, protection for thel6a-hydroxy, 17ahydroxy, or 2l-hydroxy substituent can be effected byforming the lower alkyl ortho ester thereof, i.e. 160:,1711- or 170:,2l-lower alkyl ortho esters. A suitable ether protecting group is, forexample, the tetrahydropyranyl ether. Others are arylmethyl ethers suchas, for example, the benzyl, benzhydryl and trityl ethers, or u-loweralkoxylower alkyl ethers, for example, the methoxymethyl, or allylicethers.

In compounds containing the dihydroxyacetone side chain at C-l7 (forexample, compounds of Formula V wherein R is hydroxy), the side chain atC-17 can be protected by forming the 17,20;20,2l-bis-methylenedioxygroup or by forming a 17,21-acetal or ketal group, or by forming a17,2l-diester. The 17,2l-acetal or ketal and 17,2l-diester hinder theZO-ketone group and minimize the possibility of its participating inunwanted side reactions. On the other hand, thel7,20;20,2l-bis-methylenedioxy derivatives actually convert the ketoneto a non-reactive derivative. When both a l6a-hydroxy and l7a-hydr0xysubstituent are present, these groups can be protected via formation ofa 160:,l7ct-21C6t21l or ketal. The various protecting groups mentionedabove can be removed by means known per se, for example, by mild acidhydrolysis.

In compounds wherein there is present neither a 17mhydroxy nor2l-hydroxy substituent but there is present a ZO-oxo group, the ZO-oxogroup can be protected via reduction to the corresponding carbinol(hydroxy) group. Thus, for example, the 17-acetyl side chain can beprotected via conversion to a l7-(a-hydroxyethyl)-side chain.Regeneration of the 17-acetyl side chain can be simply eflfected viaconventional oxidation means, for example, via oxidation with chromiumtrioxide in an organic solvent such as glacial acetic acid. Similarly incompounds containing a l7-oxo, this group can be protected by reductionto the corresponding carbinol (hydroxy) group. Thus, the l7-oxo groupcan be reduced to a 17fi-OH, l7a-H moiety, from which, when desired, thel7-oxo moiety can be regenerated by oxidation, as described above.Furthermore, a ZO-hydroxy or 17,8-hydroxy group, can itself be protectedby esterification, for example, with a lower alkanoic acid such asacetic acid, caproic acid, or the like; or by etherification withmoieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl,or the like.

The l6ot-l7oc or l7a,2l-acetals and ketals above discussed can be formedby reacting l6a,l7oc-bis-hydroxy or 17a,2l-bis-hydroxy startingmaterials with an aldehyde or a ketone; preferably it is done byreacting a simple acetal or ketal (i.e. a lower alkylene glycol acetalor ketal of a suitable aldehyde or ketone) with the moieties sought tobe protected.

Suitable aldehydes and ketones include lower alkanals of at least twocarbon atoms, such as paraldehyde, propanol and hexanal; di(loweralkyl)ketones, such as acetone diethylketone, dibutylketone,methylethylketone, and methylisobutylketone; cycloalkanones, such ascyclobutanone, cyclopetanone and cyclohexanone; cycloalkyl (loweralkanals), such as cyclopentylcarboxaldehyde andcyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such ascyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkylketones, such as dicyclopentyl ketone, dicyclohexyl ketone andcyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones,such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenylketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolylketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such ascyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-loweralkyl ketones, such as cyclopentyl benzyl ketone and cyclohexylphenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkylketones, such as cyclopentylmethyl benzyl ketone; halolower alkanals,such as chloral hydrate, trifluoroacetaldehyde hemiacetal, andheptafiuorobutanol ethyl hemiace tal; halo-lower alkanones, such as1,1,l-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, suchas benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde andp-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g. o-anisaldehyde),di(lower alkoxy)benzaldehydes (e.g. veratraldehyde),hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes(e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g. o-p-dimethylbenzaldehyde); mono= cyclic carboxylicaromatic lower alkanals, such as phenylacetaldehyde,u-phenylpropionaldehyde, fi-phenylpropionaldehyde,4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy,hydroxy and lower alkyl cyano derivatives thereof; monocycliccarbocyclic aromatic ketones, such as acetophenone,ot,ot,oc-t1'iflll010- acetophenone, propiophenone, butyrophenone,valerophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenoneand p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones(e.g. p-anisyl methyl ketone); di(lower alkoxy) phenyl lower alkylketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl loweralkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl loweralkyl ketones (o,p-Xylyl methyl ketone; benzophenone, and mono-orbis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivativesthereof; monocyclic carbocyclic aromatic lower alkanones, such as1-phenyl-3-butanone and 1-phenyl-4-pentanone, and aromaticallysubstituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the1604,1704- or l7a,2l-bis-hydroxy grouping form an acetal or ketal groupof the formula wherein P is individually selected from the groupconspecifically mentioned, but it should be understood that wherein Xhas the same meaning as above and D represents the carbon and hydrogenatoms necessary to complete the steroid D-ring, as well as the atoms inthe substituents in the 16- and 17-positions, as defined in Formulae I-Vabove. Thus, 9B,10a-androstanes of Formula I can be prepared from95,10fi-desA-androstan-S-ones of the formula I 3O I X (VII) wherein R RR and X have the same meaning as above. Similarly,9,3,10oz-8JldIOSi3Il6S of Formula II can be prepared from95,1OB-desA-androstan-S-ones of Formula VIII and 9B,l0a-androstanes ofFormula III from 9p,IOB-desA-androstan-S-ones of Formula IX.

wherein R R and X have the same meaning as above. Moreover, 95,10a-17B-pregnanes of Formulae IV and V can be prepared from 9,8,l0a-desA-pregnan--ones of Formulae X and XI, respectively.

wherein R';,, R R and X have the same meanings as above.

The conversion of a 95,10,6-desA-compound of Formula VI to a9fi,10e-steroid of Formulae I-V (i.e., VII- 1, VIII- 11, IX III, X IVand XI- V) is eifected by condensing the 9e,10(3-desA-compound with acompound selected from the group consisting of lower alkyl vinyl ketone(as well as substitutes therefor such as l-tertiary amino-3-butanone,l-tertiary amino-B-pentanone and quaternary ammonium salts thereof), 1,3dichlorobut-2-ene, 1,3-dichloropent-2-ene, 1-Q-butan-3-one,l-Q-butan-3-0ne lower alkylene ketal, 1-Q-butan-3-ol, 1-Q-butan-3-olether, esterified 1-Q-butan-3-ol, l-Q-pen tan-3-one, 1-Q-pentan-3-onelower alkylene ketal, l-Q- pentan-3-ol, l-Q-pentan-B-ol ether oresterified l-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the formertwo being preferred. Methyl vinyl ketone and l-tertiary amino-3-butanoneare the preferred reagents, and the former is especially preferred.Prior to the condensation it is desirable to protect the ZO-keto grouppresent in compounds of Formulae X and XI, then it is not necessary toprotect l6u,l7ot or 2l-hydroxy groups which are present, but groupsprotecting these moieties can be retained through the condensationreaction.

The above indicated substitutes for lower alkyl vinyl ketones arecompounds wherein the vinyl moiety is replaced by a moiety of theformula wherein each R is lower alkyl or taken together both Rs arelower alkylene, oxa-lower alkylene or aza-lower alkylene. Such moietiesare, for example, dimethylamino, diethylamino, pyrrolidino, piperidino,morpholino, or the like. The quaternary ammonium salts thereof areformed via the utilization of conventional quaternizing agents, forexample, lower alkyl or phenyl-lower alkyl (especially benzyl) halides,mesylates or tosylates.

When a lower alkyl vinyl ketone or substitute therefor,

' 1-Q-butan-3-one or 1-Q-pentan-3-one is used as the reaction partnerfor the condensation, ring closure to ring A (containing a 3-oxo moiety)of the desired 9,8,10u-steroid of Formulae I-V occurs simultaneouslywith the condensation. However, when 1,3-dichlorobut-2-ene,1,3-dichloropent-Z-ene, l-Q-butan-B-one lower alkylene ketal, l-Q-'butan-3-ol, 1-Q-butan-3-ol ether, esterified 1-Q-'butan-3-ol,l-Q-pentan-3-one lower alkylene ketal, 1-Q-pentan-3-ol, 1-Q-pentan-3-olether, or esterified l-Q-pentan-B-ol is used as the reaction partner asubsequent step to generate the 3-oxo moiety is required. When1-Q-butan-3-ol or 1- Q-pentan-3-ol is used as the reaction partner, theoxo moiety can be generated by oxidation and for this purpose, it issuitable to use oxidation means known per se, for example, chromic acid,chromium trioxide in acetic acid or the like. When esterified oretherified l-Q- butan-3-ol or esterified or etherified 1-Q-pentan-3-olis used as the reaction partner, hydrolysis of the esterified oretherified hydroxy group should be efiected prior to oxidation. Suitableester forming moieties are, for example, carboxylic acids, eg loweralkanoic acid such as acetic acid, benzoic acid, and the like; andhydrolysis of the reaction products obtained by reacting such l-Q-butan-3-ol or l-Q-pentan-3-ol esters is suitably conducted thy alkalinehydrolysis, e.g., via the use of an aqueous alkali metal hydroxide suchas aqueous sodium hydroxide. Suitable ethers are, for example, loweralkyl ethers, i.e. 3-methoxy, 3-ethoxy or the like; and these aresuitably hydrolyzed by acid hydrolysis, eg via the use of an aqueousmineral acid such as hydrochloric acid, sulfuric acid or the like. Whena 1-Q-butan-3-one lower alkylene ketal or a l-Q-pentan-3-one loweralkylene ketal is used as the reaction partner, mild acid hydrolysis ofthe ketal moiety results in generation of the 3-oxo moiety. Finally,when 1,3-dichlorobut-3-ene or 1,3-dichloropent-3-ene is used as thereaction partner, the 3-oxo moiety can be generated by treatment with aconcentrated mineral acid, preferably a strong acid such as hydrochloricacid or sulfuric acid. It should be noted, that 1,3-dichlorobut 2 oneand 1,3-dichloropent-2-ene may be used as reaction partners withcompounds of Formulae X and XI, but not with the 17a-lower alkyl,alkenyl or alkynyl compounds of Formulae VIII-IX. As will be apparent,when a reaction partner based on butane (i.e. having a four carbon atomskeleton) is utilized a compound of Formulae IV wherein Y is hydrogen isobtained. Similarly, when a reaction partner based on ,pentane isutilized a compound of Formulae IV wherein Y is methyl is obtained.

In addition to the preparation of compounds of Formulae IV fromcompounds of Formulae VI-XI by the use of the above mentioned reactionpartners, it is also possible by the procedures of this invention toprepare compounds of Formulae IV which, in the A-ring, in addition tocontaining an unsaturation between the 4- and 5-positions also containan unsaturation between the land 2-positions. Such 1,4-diene productscorresponding to the compounds of Formulae IV can be prepared fromcompounds of Formulae VI-XI by condensation of the latter with areaction partner selected from the group consisting of ethinyl methylketone and ethinyl ethyl ketone (as well as substitutes therefor such as[3- tertiary amino-vinyl methyl or ethyl ketone, quaternary ammoniumsalts thereof, and fi-lower alkoxy-vinyl methyl or ethyl ketone).Condensation to prepare such a 1,4-diene product corresponding to thecompounds of Formulae IV is eflfected under the same conditions as isthe condensation to prepare a compound of Formulae IV. The so-obtained1,4-dienes are useful in the same way as the correspondingly substituted4-ene-compounds of Formulae IV.

The condensation is suitably effected at, below or above roomtemperature. For example, at the reflux temperature of the reactionmedium or at ice temperature (0 C.) or below. Moreover, the condensationis suitably effected in an organic medium. Preferably the solvent is alower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, oranother non-ketonic organic solvent, such as an ether, e.g., dioxane,diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g., benzene,toluene, xylene, organic acid, such as acetic acid, or the like. Loweralkanols are the preferred solvents. It is suitable to catalyze thecondensation, and this can be effected via use of a catalyst such as analkali metal lower alkoxide, for eX- ample sodium ethoxide, potassiumt-butoxide, sodium t-amylate, or the like, alkali metal hydroxide suchas sodium, lithium or potassium hydroxide, a quaternary ammoniumhydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide suchas benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, orthe like.

When using a substitute for methyl or ethyl vinyl ketone, or for methylor ethyl ethinyl ketone, the condensation should be effected underalkaline conditons. As indicated above, among such substitutes arel-tertiary amino-3-butanone, l-tertiary amino-3-pentanone and ,8-tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary aminogroups are dilower alkylamino groups such as dimethylamino,diethylamino, pyrrolidino, piperidino, morpholino, or the like.Preferred quaternary ammonium salts of such tertiary amino groups are,for example, those formed from lower alkyl halides such as methyliodide. An exemplary [it-lower alkoxy vinyl methyl or ethyl ketone isB-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation ofdesA-androst-9-en-5-ones or desA-pregn-9-en-5-ones to9B,lOB-desA-androstan-S-ones of Formulae VII-IX or to95,lOfi-desA-pregnan-S-ones of Formulae XXI. Thus,9,6,1tlfi-desA-androstan-S-ones of Formula VII can be pre- (XII) --loweralkenyl (X III) --lower alkynyl H bl (XIV wherein R R R and X have thesame meaning as above. Also, 9B,IOfi-desA-pregnan-S-ones of Formulae Xand XI can be prepared by hydrogenation of desA- pregn-9-en-5-ones ofthe formulae wherein R' R R and X have the same meaning as above.

Prior to hydrogenation, the C-20 keto group in compounds of Formulae XVand XVI or C-l7 keto group in compounds of Formula XII should beprotected either by conversion to the corresponding carbino or byketalization as described above. The hydrogenation can, however, beetfected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting ahydrogen atom in each of the 9- and lO-positions, can alsosimultaneously effect hydrogenation of other groups in the molecule. Forexample, the C20-keto group can be hydrogenated to the correspondingcarbinol or the C-17 lower alkenyl group in com pounds of Formula XIIIor the C-17 lower alkynyl group in compounds of Formula XIV can behydrogenated to the corresponding C-l7-lower alkyl compounds. Compoundsof Formulae VIII and IX can, in turn, be prepared from compounds ofFormula VII wherein R and R together are oxo via reaction with a loweralkenyl or lower alkynyl Grignard reagent, with prior protection of theS-keto group, for example, by forming S-ketals without concurrentblocking of the 17- keto group. In the same manner compounds of FormulaeXIII and XIV can be formed from compounds of Formula XII wherein R and Rtaken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of Formulae XII-XIV and ofdesA-pregn-9-en-5-ones of Formulae XV-XVI is one of the main features ofthis invention. It is effected by catalytic hydrogenation, suitablyusing a precious metal catalyst. Suitable precious metal catalysts arepalladium, platinum, ruthenium, and rhodium, the latter two beingespecially preferred. It is particularly advantageous to use rhodium,for example, rhodium on charcoal (or carbon powder, carbon black, or thelike) or rhodium on alumina. In contrast to what would be expected, ithas been found that such a catalytic hydrogenation of a compound ofFormulae XII-XVI gives a substantial yield of a compound of Formulae VIXI. In fact, it has been found that such catalytic hydrogenation gives amajor proportion of a compound of the Formulae VI-XI. This catalytichydrogenation is suitably effected in an inert organic solvent, forexample, a lower alkanol such as methanol or ethanol, an ether such asdioxane or diglyme, a hydrocarbon such as cyclo hexane, hexane, or thelike. Lower alkanols are preferred solvents. Moreover, it is suitablyconducted in the presence of an acidic or basic catalyst, for example,an alkali metal or alkaline earth metal hydroxide such as sodiumhydroxide or the like, or a mineral acid, for example, a hydrohalicacid, such as hydrochloric acid, or the like, or an organic acid such asa lower alkanoic acid, for example, acetic acid. The reaction can beconducted at, above or below room temperature, for example, from about-5 C. to about 100 C. However, it is preferably conducted at atemperature between about G C. and about 35 C.

As described above, the desA-androst-9-ene-5-ones ordesA-l7B-pregn-9-en-5-ones of Formulae XII-XVI can be prepared fromnatural steroids by a variety of methods. Thus, in one embodiment ofthis invention said desA-androst-S en-5-ones ordesA-l7B-pregn-9-en-5-ones can be prepared from steroids of the3-oxo-androst-4-ene or 3-oxo-1Tf3-pren-4-ene series by a reactionsequence which involves as a first step an oxidative ring opening ofring A of the natural steroid. For this oxidative ring opening there canbe used as starting materials, natural steroids of the3-oxo-androst-4-ene or 3-oxo-l7 9-pregn-4- one series of the formula:

(XVII) wherein X is a substituent in the 6-position selected from thegroup consisting of hydrogen, lower alkyl, lower alkylthio and loweralkanoylthio or a substituent in the 7-position selected from the thegroup consisting of hydrogen, lower alkyl, lower alkylth-io, loweralkanoylthio and halogen, and Z represents the carbon and hydrogen atomsnecessary to complete the steroid D-ring, as well as the atoms in thesubstituents in the 16- and l7-positions as defined in Formulae I, IV,and V above. The oxidative ring opening of a natural steriod of FormulaXVII yields a 5-oxo-3,5-seco-A-norandrostan-3-oic acid or a5-oxo-3,5-seco-A-nanpregnan-3-oic acid of the formula HOOG (XVIII)wherein X and Z have the same meaning as above. The oxidative ringopening of the compound of Formula XVII can be performed by a variety ofmethods. In a preferred embodiment it is effected by ozonolysis. Theozonolysis is suitably carried out in an organic solvent, for example,acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, orthe like, or a mixture of two or more of such solvents such as ethylacetate/acetic acid, ethyl acetate/methylene chloride or the like.Moreover, the ozonolysis is advantageously conducted at below roomtemperature. Thus, it is preferably conducted at a temperature betweenabout -70 C. and about 25 C. The resulting ozonides can be decomposed byconventional means, for example, by treatment with water, hydrogenperoxide in Water, acetic acid or ethyl acetate, or the like. Theoxidative ring opening of a compound of Formula XVII to a compound ofFormula XVIII can also be effected by other oxidation means, forexample, by treatment with hydrogen peroxide. It should be noted that anoxidative ring opening by either ozonolysis or by treatment withhydrogen peroxide, does not require protection of any of thesubstituents at Cl6 or Cl7. However, as stated above, it may bedesirable to protect these substituents against some subsequent reactionin the total reaction sequence being practiced. On the other hand, theoxidative ring opening can also be effected by oxidation with chromiumtrioxide or via treatment with sodium periodate and potassium permangatein potassium carbonate solution and in these oxidation means are used,it is necessary to protect any secondary hydroxy groups which might bepresent such as a 16,176- or 21- hydroxy group; preferably, for thepurpose of this reaction, with non-aromatic protecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained5-oxo-3,5-seco-A-norandrostan-3-oic acid or5-oxo-3,5-seco-A-norpregnan-3-oic acid of Formula XVIII is convertedinto a mixture of a IOu-desA-andrQstan-S- one and aIOfl-desA-androstan-S-one or a mixture of a 10u-desA-pregnan-5-one and al0l8-desA-pregnan-5-one as illustrated below:

HET XVIII H C H a (Q 2 J .J g alkali metal salt of XX III g 1130 5 I H3011 H H o o x x (XIX) (XX) wherein in Formulae XIX and XX, X and Z havethe same meaning as above. The compounds of Formula XIX are1OoL-dESA-filldfOSlflIl-S-OHCS or ltla-desA-pregnan-S- ones, dependingon the meaning of Z, and the compounds of Formula XX areIOfl-desA-androstan-S-ones or IO S-deSA- regnan-S-ones. The conversionof a compound of Formula XVIII into the compounds of Formulae XIX and XXis effected by pyrolysis. In effecting, the pyrolysis, it is desirableto convert the 3-0ic acid of Formula XVIII into a corresponding metalsalt, for example, an alkali metal salt such as the sodium or lithiumsalt. This conversion to a metal salt can be effected prior topyrolysis, e. g., by treating the acid with sodium hydroxide or in situduring [the course of the pyrolysis, e.g., by fusing the 3-oic acid witha mixture of sodium acetate and potassium acetate. The pyrolysis can beconducted at atmospheric pressure or in a vacuum. One preferableembodiment is to conduct the pyrolysis in a vacuum, at a temperaturefrom about 200 C. to about 350 C. in the presence of a proton acceptor,e.g. an alkali metal or alkaline earth metal salt of a weak organicacid, for example, potassium acetate, sodium acetate, sodiumphenyl-acetate, sodium bicarbonate, or the like; especially preferred isa a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it isadvantageous to conduct the pyrolysis under alkaline conditions, i.e. ata pH greater than 7. The pyrolysis can be effected in solution or byfusion. An especially preferred method of effecting the pyrolysis is byfusion of an alkali metal salt of a weak acid, for example, an organiccarboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoicacid such as phenyl-acetic acid. Another method of effecting thepyrolysis is to heat, preferably at atmospheric pressure, a solution ofan alkali metal salt, such as the sodium or lithium salt, of a 3-oicacid of Formula XVIII in a basic organic solvent. The basic organicsolvent should, of course, be one which is in the liquid state at thetemperature at which the pyrolysis is effected. Thus, the pyrolysis canbe effected at a temperature up to the boiling point of the basicorganic solvent being used. Suitable basic organic solvents are, forexample, nitrogen containing organic solvents such as piperidine,pyridine, isoquinoline, quinoline, triethanolamine, or the like. Whenutilizing this approach using a basic organic solvent it is suitable toheat to temperature between about 200 C. and about 300 C., andpreferably between about 230 C. and about 260 C. A preferred basicorganic solvent for the pyrolysis of 'a salt of a compound of FormulaXVIII to compounds of Formulae XIX and XX is quinoline. If a basicorganic solvent is used which boils substantially below 200 C. atatmospheric pressure, it is suitable to conduct the pyrolysis in asealed tube or an autoclave.

In another aspect, compounds of Formula XIX can be prepared fromcompounds of the formula (XIX A) wherein X and Z have the same meaningas above. The compounds of Formula XIX can be prepared from compounds ofFormula XIX A in the same manner that compounds of Formula XIX areprepared from compounds of Formula XVII, i.e. by oxidative ring openingof the A-ring of a compound of Formula XIX A followed by elimination ofthe residue of the A-ring, to yield a compound of Formula XIX. Theoxidative ring opening of the compound of XIX A can be performed byozonolysis as described above for the conversion of a compound ofFormula XVII to a compound of Formula XVIII. Such ozonolysis of acompound of Formula XIX A yields a compound of the formula (XIX B)wherein X' and Z have the same meaning as above, and A is carboxy orformyl. A compound of Formula XD( B can then be converted to a compoundof Formula XIX. This removal of the residue of the A-ring, i.e.decarboxylation and deformylation, can be effected by heating in anacidic or basic medium. It is preferred to heat to the refluxtemperature of the medium which is preferably an inert organic solventsuch as a lower alkanol, e.g. ethanol, dioxane, ether or the like. Thedecarboxylation and deformylation yields mainly a compound of FormulaXIX, but also a minor yield of the corresponding 10B-isomer of FormulaXX.

Compounds of Formula XIX can also be formed from a compound of FormulaXVIII via the formation of an enol-lactone of a compound of FormulaXVII-I, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a4-oxopregn-5-en-3-one of the formula:

(XXI) wherein X and Z have the same meaning as above, which can then bereacted with a Grignard reagent, such as phenyl magnesium bromide orphenyl lithium, to form the resulting aldol of, for example, the formula06115 OR (XXII) wherein X and Z have the same meaning as above, which,upon treatment with an alkali metal hydroxide, such as potassiumhydroxide, at an elevated temperature, for example, from about 200 C. toabout 240 C., is converted to the corresponding 10a-desA-androstan-5-oneor lOa-desA-pregnan-S-one of Formula XIX.

It should be noted that though the pyrolysis of a compound of FormulaXVIII yields both the lOfl-compounds of Formula XX and the l0u-compoundsof Formula X'IX, and though either of these isomers can be used in thesubsequent halogenation and dehydro-halogenation steps of this reactionsequence, it is sometimes preferable to convert the lOB-compound ofFormula XX into the corresponding wot-compound of Formula XIX. Thisconversion can be effected by treating a IO/R-desA-androstan- 5-one orIOB-desA-pregnan-S-one of Formula XX with any base capable of producinga carbanion; for example, it is suitable to use an alkali metal loweralkoxide in an organic solvent such as a lower alkanol, for example,

sodium ethoxide in an ethanol solution or sodium methoxide in a methanolsolution.

The above-discussed conversion via the alkali metal salt and pyrolysisof compounds of Formula XVIII to compounds of Formulas XIX and XX can beeffected without protection of any of the substituents which might bepresent at C-16 or -17. However, if it is desired for either precedingor succeeding reaction steps of the total reaction sequence, theconversion of a compound of Formula XVIII to compounds of Formulas XIXand XX can be elfected with protecting groups present on sub stituentsin the C-l6 or 0-17 position.

As stated above, the a-desA-andrQStan-S-ones or 100:-desA-pregnan-S-ones of Formula XIX or the 10,6-desA- androstan-S-ones ofl0fi-desA-pregnan-5-ones of Formula XX can be converted via a two-stepsequence of halogenation and dehydrohalogenation into the desiredstarting material desA-androst-9-en-5-one or desA-pregn-9-en-5- one ofFormulas XII, XV, and XVI.

In a preferred embodiment a 10a-desA-androstan-5- one or a1'0a-desA-pregnan-5-one of Formula XIX is subjected to the two-stepsequence of halogenation and dehydrohalogenation. Halogenation of acompound of Formula XIX or a compound of Formula XX yields a mixture ofcorresponding halogenated compounds including one of the formula H z Halj j TIL i i i H H36 H 0 x' (XXIII) wherein X and Z have the same meaningas above, and Hal is a halogen atom (preferably Br or Cl).Dehydrohalogenation of a compound of Formula XXIII then yields a desiredstarting material of Formulas XII, XV and XVI. Keto groups, except forthe S-keto group, may require protection prior to the halogenation. Inthe case of compounds of Formulas XIX and XX containing the C-l7dihydroxyacetone side chain, represented in Formula V wherein R ishydroxy, this protection can be effected by formation of the17a,20;20,21-bis-methylenedioxy derivative. In other cases wherein a C17oxo or C-ZO oxo group is present, protection can be elfected byreduction to the corresponding carbinol either directly prior to thehalogenation step or prior to some other step in the reaction sequenceleading to the compounds of Formulas XIX and XX.

The halogenation can be elfected with halogenating agents such asbromine, sulfuryl chloride, or the like. Bromination is especiallypreferred. The bromination is suitably effected by treatment withbromine at room temperature or below, preferably at ice temperature-orbelow. Suitably it is conducted in an organic medium; for example, anorganic acid such as acetic acid; an ether such as an anhydrous ether,dioxane, tetrahydrofuran; a chlorinated organic solvent such asmethylene chloride, chloroform, carbon tetrachloride; or the like; withthe addition of hydrogen bromide as a catalyst. When effectinghalogenation with sulfuryl chloride, it is suitable to use the same typeof organic medium as when brominating; and suitable catalysts are, forexample, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of Formula XXIII ispreferably conducted under mild dehydrohalogenating conditions; forexample, by the use of an alkali metal carbonate {c.g. lithiumcarbonate) or an alkali metal halogenide (e.g. a lithium halide) in anorganic solvent such as a di-lower alkyl-formamide, or with an organicbase such as collidine, pyridine, or the like. The dehydrohalogenationis advantageously conducted at slightly elevated temperatures, forexample, from about 50 C. to about 150 0., preferably from about C. toabout 120 C.

Separation of the desired product desA-androst-9-en-5- one ordesA-pregn-9-en-S-one of Formulas XII, XV and XVI can be eifected byconventional means. As indicated above the halogenation procedure mayresult in halogenated lay-products in addition to the desired intermediate of Formula XXIII. Accordingly, the separation is preferablyeffected after first subjecting the reaction mixture to dehalogenatingconditions in order to dehalogenate the halogenated by-products formedby the halogenation procedure, but not dehalogenated by thedehydrohalogenation. Following such dehalogenation the reaction mixturecan then easily be separated by conventional means, for example, bycolumn chromatography, to yield the desired compound of Formulas XII,XV, XVI. An exemplary dehalogenation means is treatment with zinc andsodium acetate in an acetic acid solution at an elevated temperature,for example, about 80 C.

In the case of compounds of Formula XIX or XX which contain a halogenatom on a carbon atom directly adjacent to a keto group, it ispreferable to protect such a halogen atom against dehalogenation priorto subjecting the compound of Formula XIX or XX to the two step sequenceof halogenation and dehydrohalogenation of this embodiment. Such agrouping, containing a halogen atom on a carbon atom directly adjacentto a keto group, is illustrated in a compound of Formula IV or V whereinR or R is halogen. Thus, if 10w or IOfi-desA- pregnan-S-one of FormulaXIX or XX containing a 17(1- or ZI-halo substituent is to be subjectedto the halogenation-dehydrohalogenation sequence it is desirable tofirst effectprotection of the 17(1- or 21-halosubstituent. Thisprotection can be effected, for example, by ketalization of the 20-oxogroup.

As stated above, the desired desA-androst-9-en-S-ones or desA pregn 9 en5 ones starting materials can also be prepared from steroids of the 3oxo androst- 4-ene or 3-oxo-l7fi-pregn-4-ene series containing an 11-hydroxy substituent. In one embodiment an ll-hydroxy steroid of theformula now/ wherein X and Z have the same meaning as above, is reactedwith an acid or a reactive derivative thereof to form a leaving group inthe ll-position. By reactive derivative is meant, for example, a halide,e.g. a chloride, an anhydride, or the like. Though either or 11ozhydroxystarting materials can be used, it is preferable to utilize a-hydroxycompounds of Formula XXIV as starting materials. Prior to theesterification reaction, it is preferable to protect hydroxy groupspresent in the C- 16, 0-17, or C-2l position. Suitable acids for theesterification of the ll-hydroxy group, which can be used to form aleaving group in the ll-position are inorganic acids such as phosphoricacid, organic carboxylic acids such as anthraquinone fi-carboxylic acidor organic sulfonic acids, for example, toluene-sulfonic acids,especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such asmethane-sulfonic acid and nitrophenyl-sulfonic acids, especiallyp-nitrophenylsulfonic acid. Especially preferred as the leaving group inthe ll-position is a lower alkylsulfonyloxy group such as the mesoxygroup. However, when it is desired to react a compound .of Formula XXIVwith a sulfonyloxy forming moiety, them a compound of Formula XXIV havng an Ila-configuration should be used as (XXIV) 17 a starting material.The above described esterification of ll-hydroxy steroid startingmaterials of Formula XXIV yields compounds of the formula X (XXV)wherein X and Z have the same meaning as above, and LO represents theleaving group.

In the next step of this reaction sequence, the soformed 11 (esterifiedhydroxy) compound of Formula XXV is subjected to an oxidative ringopening of the A- ring to yield the corresponding ll-(esterifiedhydroxy)-- oxo-3,5-seco-A-norandrostan3-oic acid .or ll-(esterifiedhydroxy)-5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula HsC H3O IJ (/N/i i H H l HOOC y 0 X (XXVI) wherein X, Z and LO have the samemeaning as above. The oxidative ring opening of the A-ring of a compoundof Formula XXV to a compound of Formula XXVI can be effected byozonolysis as described above for the oxidative ring opening of theA-ring of a compound of Formula XVII to a compound of Formula XVIII.Pyrolysis of the so-formed compound of Formula XXVI under the conditionsdescribed above for the pyrolysis of a compound of Formula XVIII tocompounds of the Formulas XIX and XX directly yields the desired desA-androst-9-en-5-one or desA-pregn-9-en-5-one of Formulas XII, XV, XVI.Thus, pyrolysis of a compound of Formula XXVI directly results inelimination of the leaving group in the ll-position as well as asplitting off of the residue of ring A attached to the 10-position. Thisprocedure of starting from an ll-hydroxy steroid (preferablylla-hydroxy) of Formula XXIV and proceeding through intermediates ofFormulas XXV and XXVI to compounds of Formulas XII, XV, XVI, representsa particularly elegant procedure for preparing the latter compounds. Anespecially preferred method of effecting the pyrolysis of a salt of a3-oic acid of Formula XXVI is the method described above wherein thesalt of the 3- oic acid is heated in a liquid basic organic solvent.Especially preferred solvents for the pyrolysis of a salt of a compoundof Formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of acompound of Formula XXVI involves two separate chemical attacks; onebeing the elimination of the ll-leaving group and the other being thesplitting off of the A-ring residue. Instead of effecting these twoattacks simultaneously, as described above, it is also possible toeffect them sequentially by just prior to formation of the salt,effecting elimination of the leaving group of the compound of FormulaXXVI. This elimination yields a A -seco acid of the formula wherein Xand Z have the same meaning as above. The elimination can be effected byany conventional elimination means. It is suitably conducted underalkaline conditions in an anhydrous organic solvent. Preferably, it iseffected by heating, i.e. at a temperature between about roomtemperature and the reflux temperature of the reaction mixture. Thus,treatment of a compound of Formula XXVI with either an inorganic ororganic acid or base results in the formation of the desired compound ofFormula XXVI A. Preferably a weak base is used, for example, a salt of acarboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or analkaline earth metal, for example, sodium acetate, potassium acetate, orthe like. As indicated, the elimination is suitably conducted in ananhydrous organic solvent; suitable are solvents such as diloweralkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g.acetic acid, or the like. When a proton accepting solvent, such asdimethylformamide, is used, it itself can serve as the base for thepurpose of this elimination reaction; i.e. if the solvent is basic thenthe elimination can be conducted without the addition of a separatebasic material. Similarly, if the solvent is acidic, then theelimination can be conducted without the addition of a separate acidicmaterial.

After the elimination is effected the A -seco acid product of FormulaXXVI A can then be converted to a salt, for example, an alkali metalsalt, and the so-formed salt pyrolyzed according to the conditionsdescribed above for the pyrolysis of a compound of Formula XXVI tocompounds of Formulas XII, XV and XVI.

After the above-described ll-leaving group elimination and A-ringresidue splitting, conducted either simultaneously or sequentially, thedesired desA-9-en-5-one compounds of Formulas XII, XV and XVI can beisolated by conventional means. However, it has been found particularlysuitable with compounds of Formulas XV and XVI to isolate by forming thedisemicarbazone of the pyrolysis product and then regenerating therefromthe desired 5,20-dione of Formula XV or XVI, or if the 20- oxo group hasbeen protected, for example, by reduction to a ZO-hydroxy moiety, byforming the semicarbazone at the 5-position and then regeneratingtherefrom the desired S-one compound.

In yet another embodiment of this invention starting material ll-hydroxysteroids of Formula XXIV can be directly subjected to an oxidative ringopening of the A-ring by ozonolysis or treatment with hydroxideperoxide, as described above for the oxidative ring opening of theA-ring of a compound of Formula XVII to a compound of Formula XVIII.This oxidative ring opening of the A-ring of a compound of Formula XXIVyields an 11 hydroxy-5-oxo-3,5-seco-A-norandrostan-5-oic acid 3,ll-lactone or an 11-hydroxy-3-oxo-3,S-seco-A-norpregnan-3-oic acid3,11-lactone of the formula H H30 XXVII H0 H30 E Z J alkali metal salt I3 H3O H I (XXVIII) (XXIX) wherein in Formulas XXVIII and XXIX, X and Zhave the same meaning as above. This pyrolysis of an alkali metal saltderived from a compound of Formula XXVII can be effected under the sameconditions as described above for the pyrolysis of a compound of FormulaXVIII to compounds of the Formulae XIX and XX. Though either thelop-compound of Formula XXVIII or the 100:- compound of Formula XXIX canbe subjected to the subsequent steps of this reaction sequence, it issuitable to utilize the IOfi-compound of Formula XXVIII. Conversion ofthe wot-compound of Formula XXIX to the B-compound of Formula XXVIII canbe effected under the same conditions as described above for theconversion of the compound of Formula XX to a compound of Formula XIX.

In the next step of this reaction sequence, the ll-hydroxy compound ofFormula XXVIII or of Formula XXIX can be subjected to esterificationwhereby to convert the ll-hydroxy group to a leaving group in the 11-position. This esterification can be effected with the same acids oracid derivatives and in the same manner as described above for theesterification of a compound of Formula XXIV to a compound of FormulaXXV. As in that instance, it is also preferred in the present instanceto form a mesoxy leaving group in the ll-position, though, of course,other leaving groups as described above are useful for the instantpurpose. There is thus obtained a compound of the formula HaC (XXX)wherein X, Z and LO have the same meanings as above. The leaving groupcan then be eliminated from the 11- position of a compound of FormulaXXX resulting in a direct formation of a desA-androst-9-en-5-one or adesA- pregn-Q-en-S-one of Formulae XII, XV, XVI. This elmination can beeffected by any conventional elimination means. It is suitably conductedunder alkaline conditions in an anhydrous organic solvent. Preferably,it is effected by heating, i.e. at a temperature between about roomtemperature and the reflux temperature of the reaction mixture. Thus,treatment of a compound of Formula XXX with either an inorganic ororganic base results in the formation of the desired compound ofFormulae XII, XV, XVI. Preferably a weak base is used, for example, asalt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkalimetal or an alkaline earth metal, for example, sodium acetate, potassiumacetate, or the like. As ind a ed, he elimination is sui a ly c n uctedin a anhydrous organic solvent; suitable are solvents such as diloweralkyl-formamides, e.g. dimethyl formamide, lower alkanoic acids, e.g.acetic acid, or the like. When a proton accepting solvent, such asdimethyl formamide, is used, it itself can serve as the base for thepurpose of this elimination reaction; i.e. if the solvent is basic thenthe elimination can be conducted without the addition of a separate basematerial.

In another aspect, compounds of Formula XXX can be prepared fromcompounds of the formula (XXX A) wherein X, Z and LO have the samemeanings as above. The compounds of Formula XXX A can be prepared fromcorresponding ll-hydroxy compounds by esterification as described abovefor the preparation of compounds of Formula XXV from compounds ofFormula XXIV. The compounds of Formula XXX can be prepared fromcompounds of Formula XXX A in the same manner that compounds of FormulaXXX are prepared from compounds of Formula XXV, i.e. by oxidative ringopening of the A-ring of a compound of Formula XXX A followed byelimination of the residue of the A-ring to yield a compound of FormulaXXX. The oxidative ring opening of the compounds of Formula XXX A can beperformed by ozonolysis as described above for conversion of a compoundof Formula XXV to a compound of Formula XXVI. Such ozonolysis of acompound of Formula XXX A yields a compound of the formula (XXX B)wherein X, Z and LO have the same meaning as above. A compound ofFormula XXX B can then be converted to a compound of Formula XXX. Thisremoval of the residue of the A-ring, i.e. decarboxylation, can beeffected as described above for the conversion of a compound of FormulaXIX B to a compound of Formula XIX.

The compounds of Formulae I-V preparable by the methods of thisinvention are not only pharmaceutically useful compounds as describedabove, but also are themselves useful as intermediates for other9,8,10oc-st6r0ids; for example, compounds wherein X is hydrogen or loweralkyl can be modified so as to introduce unsaturation between C-6 andC-7. This can be effected by dehydrogenation means, for example, byhalogenation followed by dehydrohalogenation or by means of2,3-dichloro- 5,6-dicyanobenzoquinone, according to known methods. Thus,for example, a 95,l0a-progesterone of Formula IV wherein X is hydrogenor lower alkyl can be converted to a 9B,10a-pregna-4,6-dien-3,20dione.

A further embodiment of this invention comprises the preparation of9,8,10a-steroids of Formulae I-V containing an ll-hydroxy substituent.This can be effected by utilizing an1l-hydl'OXY-IOwdCSA-aRdIOStZII-S-OIIC or1l-hydroxy-IOa-deSA-pregnan-S-One of Formula XXIX or anll-hydroxy-lOfl-desA-androstan-S-one or 11-hydroxy-IOB-desA-pregnan-S-one of Formula XXVIII as the startingmaterials. It is preferred in this embodiment to use the IOB-isomers ofFormula XXVIII as starting materia s. As a firs st p i this the li ht drxy group of 21 the compound of Formula XXVIII or XXIX should beprotected. This is suitably elfected by esterification, preferably witha carboxylic acid, for example, a lower alkanoic acid such as aceticacid, benzoic acid, or the like. Conversion of the so-obtainedll-esterified hydroxy compound then yields an ll-(esterifiedhydroxy)-desA-androst-9-en- S-one (i.e. a compound of Formula XIIcontaining an 11- esterified hydroxy moiety) or an ll-esterifiedhydroxydesA-pregn-9-en-5-one (i.e. a compound of Formulae XV XVIcontaining an lla-esterified hydroxy moiety). This conversion can beeffected by halogenation followed by dehydrohalogenation, as describedabove for the conversion of a compound of Formula XIX or XX to acompound of Formulae XII, XV or XVI. Catalytic hydrogenation of theso-obtained compound of the formula H C EOM-| H z a M "Q X (XXXI)wherein X and Z have the same meaning as above, and E is an esterifiedhydroxy group as described above in this paragraph, yields anll-esterified hydroxy-desA- 96,10B-androstan-5-one or ll-esterifiedhydroxy-desA-9,8, IOB-pregnan-S-one, of the formula (XXX II) wherein X,Z and E0 have the same meaning as above. This hydrogenation can beconducted in the same manner as described above for the hydrogenation ofa compound of Formulae XII-XVI to a compound of Formulae VII, X, XI.Also, compounds of Formula XXXII containing a l7-oxo moiety can beconverted to a corresponding compound containing a l7B-hydroxy,l7u-lower alkenyl or lower alkynyl moiety by the methods describedabove. Also, compounds of Formula XXXII can be hydrolyzed to yieldcorresponding ll-hydroxy compounds of Formula XXXII, i.e. wherein E0 ishydroxy.

Condensation of the so-obtained compound of Formula XXXII or thecorresponding l7B-hydroxy, 17alower alkenyl or lower alkynyl compound(i.e. a compound of Formula VI containing a free or ll-esterifiedhydroxy group) then yields the desired end-product 95, lOa-steroid ofFormulae I-V containing an ll-hydroxy group. Such condensation can beeffected as described above for the preparation of a compound ofFormulae I-V from a compound of Formulae VIXI. The soobtained 98,l0a-steroids containing an ll-esterified hydroxy group can behydrolyzed to the corresponding compounds containing an ll-hydroxygroup, which latter compounds are themselves useful as intermediates,for example, the ll-hydroxy group can be oxidized by methods known perse to yield corresponding 1l-oxo steroid analogous to compounds ofFormulas I-V.

The pharmaceutically useful compounds prepared by the methods of thisinvention can be administered internally, for example, orally orparenterally, with dosage adjusted to individual requirements. They canbe administered in conventional pharmaceutical forms, e.g. capsules,tables, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of thisinvention. All temperatures are in degrees Centigrade. The Florisiladsorbent used infra is a synthetic magnesia-silica gel available fromthe Floridin Company, PO. Box 989, Tallahassee, Fla. (cf. p. 1590, MerckIndex, 7th ed., 1960). -200 mesh material was used. The moietydesignated by tetrahydropyranyloxy is tetrahydro-2-pyranyloxy. When itis stated that a procedure is effected in the cold, it should beunderstood that it is commenced at 0 C. Throughout this application whencompounds of the pregnane series are referred to it should be understoodthat it is compounds of the l7fi-pregnane series that are being referredto, unless specifically indicated to the contrary, and whether or notthe compound of the pregnane series is specifically indicated as of the17,8-series.

EXAMPLE 1 A solution of 3.2 g. of 17a-ethyltestosterone in 50 ml.methylene chloride and 25 ml. ethyl acetate was ozonized at 70(acetone-Dry Ice bath) until the solution was blue in color. Afteroxygen was passed through, the solution was evaporated at roomtemperature in vacuo. The syrupy residue 'was then dissolved in 100 ml.of glacial acetic acid, and after addition of 5 ml. of 30 percenthydrogen peroxide, left for 24 hours at 05. Following this time, it wasevaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2N sodium carbonate solution. The alkaline extract was poured in ice coldhydrochloric acid. The resultant crystalline 17ozethyl 17,3 hydroxy 5oxo 3,5 seco-A-norandrostan- 3-oic acid was filtered, washed with waterand dried. Upon being recrystallized from acetone, it melted at196-197".

EXAMPLE 2 A solution of 1.5 g. of 17a-ethyl-17B-hydroxy-5-oxo- 3,5 secoA norandrostan 3 oic acid in 100 ml. of methanol was titrated with 2 Nsodium methoxide to the reddish color of phenolphthaleine, and thenevaporated to dryness in vacuo, giving as the residue, the sodium saltof l7a-ethyl-17,8-hydroxy-5-oxo-3,S-seco-A-norandrostan- 3-oic acid. 5g. of sodiumphenylacetate was added to the residue, and the mixturepyrolyzed in vacuo 0.l mm.) at 285-290, for 2.5 hours. The sublimate wasdissolved in acetone, filtered and the filtrate concentrated in vacuo.The resultant syrupy residue was chromatographed on a 60 g. Florisil(adsorbent) column. The fractions eluted with benzene and 0.5 percentethylacetate in benzene were combined and gave17a-ethyl-l7j8-hydroxy-10adesA-androstan-S-one, M.P. 9495 afterrecrystallization from petroleum ether. The fractions eluted with 2percent and 5 percent ethylacetate in benzene were combined and gavel7a-ethyl-l7t3-hydroxy-10B-desA-androstan-S-one, M.P. 185-185.5, aftertwo recrystallizations from petroleum ether.

EXAMPLE 2a To a solution of 100 mg. of 17a-ethyl-l7B-hydroxy-IOfi-desA-androstan-S-one in 10 ml. of absolute ethanol was added oneequivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol.This reaction mixture was maintained at room temperature overnight, thenacidified with glacial acetic acid, poured in water and extracted withmethylene chloride. The extract was washed with water, dried overanhydrous sodium sulfate and concentrated in vacuo. Thin layerchromatography showed the product to be17x-ethyl-17,8-hydroxy-lOu-desA-androstan- 5-one. It was obtainedcrystalline from petroleum etherether and melted at 8995.

EXAMPLE 3 1.13 g. of 17a-ethyl-l7B-hydroxy-10a-desA-androstan- 5-one wasdissolved into ml. of anhydrous ether (or 1.13 g. of 10,8-isomer wasdissolved in 300 ml. of anhydrous ether), and after cooling in asalt-ice bath, several drops of 30 percent hydrobromic acid in aceticacid were added. This was followed by the dropwise addition during fiveminutes of 0.684 g; of bromine dissolved in 2 ml. of acetic acid. Thisaddition was synchronized with the decoloration rate of the reactionmixture. Immediately after this, ml. of a saturated solution of sodiumbisulfite and 5 ml. of 2 N sodium carbonate solution were added. Themixture was then transferred into a separatory funnel, 500 ml. of etheradded, shaken and separated. The ether part was washed with water, driedand evaporated. The resultant bromides were dissolved in 100 ml. ofdimethylformarnide, and after addition of 3 g. of lithium carbonate, thesolution was heated at 100 for 45 minutes. After cooling, it was pouredinto one liter of ether, washed with water, 1 N hydrochloric acid, 2 Nsodium carbonate, water, dried and evaporated. The residue was dissolvedin 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. ofzinc powder added, and the so-formed mixture heated minutes at 80. Itwas then poured into one liter of ethylacetate and the resultantsolution washed with saturated sodium bicarbonate, then with water,dried and evaporated. The residue was chromatographed on Florisil(adsorbent) column. The fraction with benzene and /2 percentethylacetate in benzene gave regenerated starting material. Fractionswith l and 2 percent ethylacetate in benzene gavel7e-ethyl-175-hydroxy-desA-andrest-9 en 5 one, which after sublimation(140 and 0.1 mm. Hg vacuum), was obtained as a glass. 36.6 (c.=l, CHClEXAMPLE 4 A suspension of 262 mg. of 5 percent rhodium on aluminacatalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2N sodium hydroxide solution was pre-reduced, (i.e., hydrogenated at roomtemperature and atmospheric pressure). To this was added a solution of262 mg. of 17OL-BihYl-l7fi-hYClIOXY-(1ESA- androst-9-en-5-one in ml. of95 percent ethanol, and the mixture then hydrogenated at atmosphericpressure and room temperature. After one mole-equivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate evaporated in vacuo. Glacial acetic acid (1ml.) was added to the residue, which was then dissolved in 1 liter ofether. The cloudy solution which resulted was washed with 2 N Na COsolution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined productschromatographed on a Florisil (adsorbent) column. The eluates with 1percent ethyl acetate in benzene gave first crystalline fractions, whichwere followed by non-crystalline fractions. The noncrystalline fractionswere dissolved in 100 ml. of methylene chloride, and after the additionof 2.5 ml. of 2 percent CrO in 90 percent acetic acid, stirredovernight. The excess of chromic acid was removed by washing themethylene chloride solution with 10 ml. of 10 percent sodium hydrogensulfite solution, followed by washing with 2 N Na CO solution and thenwith water. It was then dried and evaporated in vacuo. The residue wasdissolved in 50 ml. of anhydrous ethanol containing 172 mg. of sodiumethoxide, and left overnight. The next day, after addition of 0.5 ml. ofglacial acetic acid, the solution was evaporated in vacuo, and theresidue was taken up in 1 liter of ether. The ether solution was Washedwith 2 N Na CO solution, then with water, dried and evaporated. Theresidue was chromatographed on Florisil (adsorbent) column and gavecrystalline 17aethyl-l7fi-hydroxy-desA-9fi,IOfl-androstan-S-oneidentical (by thin layer chromatography) with the crystalline materialobtained in the first chromatographic separation. After tworecrystallizations from ether, it melted at 142- 144; [ch ll.650[methane], c.=1.245 percent].

EXAMPLE 5 To a solution of 132 mg. of17u-ethyll7{3-hydroxydesA-9fi,10,8-androstan-5-one in 12.5 ml. ofabsolute ethand c nta g 34 mg. of sodium ethoxide, 0.15 ml. of

freshly distilled methylvinyl ketone was added. The reaction mixture wasthen refluxed for two hours in a nitrogen atmosphere. After cooling thereaction mixture, 0.1 ml. of glacial acetic acid was added thereto andthe resulting mixture was then poured into 1 liter of ether. Theresultant ether solution was washed with water, dried over anhydroussodium sulfate and evaporated in vacuo. The residue was chromatographedon fluorescent silica-gel plates, with the solvent system, 60 percentethyl acetate 40 percent heptane. The fluorescent part of the layers wasextracted with ethyl acetate. The residue obtained after evaporation ofethyl acetate was first crystallized from ether-petroleum ether, then asecond time from pure ether, yielding l7a-ethyl-9fl,IDOL-testosterone,M.P. 131- 135.

EXAMPLE 6 A solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. ofethylacetate and 50 ml. of methylene chloride was treated with ozone atuntil the solution became blue in color. Oxygen was then passed throughand the solution evaporated at room temperature in vacuo. Theso-obtained syrupy residue was dissolved in ml. of glacial acetic acid,and after the addition of 5 ml. of 30 percent hydrogen peroxide, leftfor 24 hours at 2 (in an ice box). The solution was then evaporated invacuo, and the residue triturated with ether yielding crystals.Recrystallization from acetone yielded llu-hydroxy-3,5-seco-A-nor-pregnane-5,20-dione-3-oic acid 3,1l-lactone, M.P. 253-256". [a]+193.3) (c.=1, in chloroform).

EXAMPLE 7 A methanolic solution of 7.5 g. of 11a-hydroxy-3,5- secoA-nor-pregnane-5,20-dione-3-oic acid 3,11-lactone was treated with oneequivalent of 1-0 N sodium hydroxide solution and then evaporated todryness. Sodium phenyl-acetate (26 g.) was added to the so-obtainedsodium salt and the mixture pyrolyzed at 295 for two hours in vacuo. Thecrude sublimate was chromatographed on a silica-gel column and elutedwith 10 percent ethylacetate in benzene. The amorphous solidlla-hydroxy-lOa-desA- pregnane-5,20-dione was first eluted from thecolumn. IR- spectrum in chloroform: 3620 and 3600 cm? (-OH); 1706 cm?(carbonyl group). NMR-spectrum in deuterochloroform: a doublet for10a-CH at 73.5 and 80.5 c.p.s. downfield from TMS at 60 mc./sec. Furtherelution of the column with 10 percent ethylacetate in benzene yieldedcrystalline 1la-hydroxy-lG/S-desA-pregnane-S,20-dione which wasrecrystallized from methylene chloride-petroleum ether, M.P. ISO-152;[a] +84.0 (c.=0.5 in absolute ethanol).

EXAMPLE 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml.of pyridine, there was added 100 mg. of 110:-hydroxy--desA-pregnane-5,ZO-dione. The mixture was then allowed to standovernight at 2 (in a refrigerator), then was diluted with water (100ml.) and extracted with chloroform (3x150 ml.) and methylene chloride(100 ml.). The combined organic extracts were washed with water, 1 Nhydrochloric acid and again with water, then dried over anhydrous sodiumsulfate and evaporated in vacuo. The crystalline residue wasrecrystallized from ether, giving1la-hydroxy-lOfl-desA-pregnane-S,20-dione methanesulfonate, M.P. 139l40;[0r] +46 (c.=0.5 in absolute ethanol).

EXAMPLE 9 A solution of 200 mg. of lla-hydroxy-lOB-desA-pregnane-5,2O-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed foreight hours and then evaporated to dryness. The residue waschromatographed on a Florisil (adsorbent) column. Elution with 2 percentethylacetate/benzene and evaporation of the eluant yieldeddesA-pregn-9-ene-5,20-dione in the form of colorless needles, M.P.111113. It was shown by mixed melting point to be identical with asample of the same compound prepared as described in Example 12.

EXAMPLE 10 To a solution of 20 g. of lla-hydroxy-progesterone in 150 ml.of pyridine maintained at there was added 6 ml. ofmethanesulfonylchloride, and the reaction mixture allowed to standovernight at 0. It was then diluted with a large excess of water andextracted with chloroform. The organic extracts were washed with 2 Nhydrochloric acid and water, then dried over anhydrous sodium sulfateand evaporated in vacuo. The solid residue was recrystallized frommethanol to give lla-mesyloxy-progesterone, M.P. l59.5l60; [a] |145.6(c.=l, chloroform).

EXAMPLE 1 1 A solution of 12 g. of 1la-mesyloxy-progesterone in 300 ml.of methylene chloride/ethyl acetate (2:1) was treated with ozone at 70until the solution became blue in color. The excess of ozone was removedby =bubbling oxygen through the reaction mixture for five minutes.Methylene chloride was then removed under reduced pressure, and thesolution diluted with ethyl acetate to 200 ml. After addition of 12 ml.of 30 percent aqueous hydrogen peroxide, the reaction mixture was thenallowed to stand overnight at 2 (i.e., in the refrigerator), thenevaporated to a volume of 75 ml. and diluted with 125 ml. of benzene.The aqueous solution, obtained by extraction with 8 portions of 75 ml. 2N sodium carbonate followed by combining the aqueous extracts wasacidified with cold concentrated hydrochloric acid to pH 2 and extractedwith methylene chloride. This extract was dried over anhydrous sodiumsulfate and evaporated in vacuo to dryness. The residue crystallizedwhen triturated with ether-acetone mixture, yielding crude 11amesoxy5,20 dioxo-3,5-seco-A-nor-pregnan-3-oic acid. After recrystallizationfrom acetone-petroleum ether, M.P. 152-153; [a] +47.9 (c.=1,chloroform).

EXAMPLE 12 A solution of 6 g. of lla-mesoxy-5,20-dioxo-3,S-seco-A-nor-pregnan-3-oic acid in 150 ml. of methanol was mixed with asolution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixturewas then transferred into a 1 liter sublimation flask, and evaporated todryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetateis added, and after closing the top part of the apparatus, this mixturewas prolyzed at 290 and 0.02 mm. for four hours. The product, whichcollects on the cold finger, was dissolved in ether and filtered. Thefiltrate was then exaporated to dryness. Purification of the residue bychromatography on a 40 g. silica-gel column (benzene eluant) gavecrystalline desA-pregn-9-ene-5,20-dione; M.P. Ill-113 (afterrecrystallization from ether). +56.8 (c.=0.25 percent in methanol).

EXAMPLE 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20ml. of methanol maintained at 0, there was slowly added a cooledsolution of 1.2 g. of sodium borohydride in 22 ml. methanol, and theresultant mixture was left for 72 hours at 0. It was then diluted with100 ml. of water and extracted with four 100 ml. portions of chloroform.The extract was dried over anhydrous sodium sulfate and evaporated invacuo, yielding a colorless oily product. This product was dissolved in250 ml. of chloroform and 6 g. of manganese dioxide was added to thesolution which was then stirred for 72 hours at room temperature,filtered and the filtrate exaporated to dryness in vacuo. The residuewas chromatographed on a silica-gel column and the eluates with percentethyl acetate in benzene, after concentration gave crystalline20,B-hydroxy-desA- pregn-9-en-5-one which upon recrystallization frommethylene chloride-petroleum ether formed colorless 26 needles, M.P.122-125; 33 (c.:0.5, absolute ethanol).

EXAMPLE 14 A suspension of 262 mg. of 5 percent rhodium on aluminacatalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2N aqueous sodium hydroxide was hydrogenated at room temperature andatmospheric pressure. To this was added a solution of 262 mg. of 205-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 percent ethanol, and thereaction mixture then hydrogenated at room temperature and atmosphericpressure. After one mole equivalent of hydrogen was absorbed, thereaction was stopped, and the catalyst was separated by filtration.After standing overnight the filtrate was concentrated in vacuo. To theresidue was added 1 ml. of glacial acetic acid, and it was thendissolved in 1 liter of ether. The cloudy solution was washed with 2 Naqueous sodium carbonate solution, then with water, then dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. It yieldeda colorless oil, which was chromatographed on a silica-gel column using1 percent ethyl acetate in benzene as the elutant. First eluted wasZOB-hydroxy-lOa-desA- pregnan-S-one, M.P. 107-108 afterrecrystallization from methylene chloride/petroleum ether. R.D. (inmethanol); 1500 1400 1350 1305 ---1335; [@1 1165.

Further elution yielded 20 3-hydroxy-9fi,l0fi-desA-pregnan-S-one as acolorless oil. R.D. (in methanol): [111 1400 1350 1310 EXAMPLE 15 Asuspension of 262 mg. of 5 percent rhodium on alumina catalyst in amixture of 2 ml. of 3 N aqueous hydrochloric acid and 18 ml. percentethanol was hydrogenated at room temperature and atmospheric pressure. Asolution of 262 mg. of 20fi-hydroxy-desA-pregn-9- en-S-one in 5 ml. ofabsolute ethanol was introduced into the hydrogenation flask, and thereaction mixture was then hydrogenated at room temperature andatmospheric pressure. After one mole-equivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate neutralized with 2 N aqueous sodiumhydroxide solution. An excess of 5 ml. of 2 N aqueous sodium hydroxidewas added and the solution allowed to stand overnight. Ethanol was thenremoved by evaporation at reduced pressure, and after addition of 1 ml.of glacial acetic acid, it was extracted with 1 liter of ether. Theextract was washed with 2 N aqueous sodium carbonate solution, then withwater, dried and concentrated in vacuo. It gave a colorless oil, whichwas chromatographed on a silica-gel column using 2 percent ethyl acetatein benzene as the elutant. The first fractions of the eluate yielded,upon concentration, 205- hydroxy-l0a-desA-pregnan-5-one. From theimmediately subsequent fraction, 20p-hydroxy-9/3-lOB-desA-pregnan-S- onewas obtained. Both products were identical with the same compoundsobtained in Example 14.

EXAMPLE 16 20fl-hydroxy-9fi,l0a-pregn-4-en-3-one is prepared bycondensation of 20B-hydroxy-9fi,10,8-desA-pregnan-5-one with methylvinyl ketone according to the procedure of Example 5. The product meltsat 176.5178.5; [M l43 (chloroform).

EXAMPLE 17 A medium is prepared of 20 g. of Edamine enzymatic digest oflactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrosediluted to 1 liter with tap water and adjusted to a pH of 4.3-4.5.Twelve liters of this sterilized medium is inoculated with Rhizopusnigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28using a rate of aeration and stirring such that the oxygen uptake is6.3-7 millimoles per hour per liter of Na SO according to the method ofCooper et al.,

Ind. Eng. Chem, 36, 504 (1944). To this medium containing a 24 hourgrowth of Rhizopus nigricans minus strain, 6 g. of17a-acetoxy-pregesterone in 150 ml. of acetone is added. The resultantsuspension of the steroid in the culture is incubated under the samecondttions of temperature and aeration for an additional 24 hour periodafter which the beer and mycelium are extracted. The rnycelium is thenfiltered, washed twice, each time with a volume of acetone approximatelyequal in volume to the mycelium, extracted twice, each time with avolume of methylene chloride approximately equal to the volume of themycelium. The acetone and methylene chloride extracts including solventare then added to the beer filtrate. The mixed extracts and beerfiltrate are then extracted successively with 2 portions of methylenechloride, each portion being /2 the volume of the mixed extracts andbeer filtrate, and then with 2 portions of methylene chloride, eachportion being A the volume of the mixed extracts and beer filtrate. Thecombined methylene chloride extracts are then Washed with 2 portions ofa 2 percent aqueous solution of sodium bicarbonate, each portion beingthe volume of the combined methylene chloride extracts. The methylenechloride extracts are then dried with about 3-5 g. of anhydrous sodiumsulfate per liter of solvent, and then filtered. The solvent is thenremoved from the filtrate by distillation, and the residue is dissolvedin a minimum of methylene chloride, filtered and the solvent evaporatedfrom the filtrate. The resulting crystals are then dried and washed fivetimes, each time with a 5 ml. portion of ether per gram of crystal. Thecrystals are then recrystallized from ether giving17a-acetoxy-1la-hydroxy-pio gesterone.l7ot-acetoxy-llot-mesoxy-progesterone is prepared oy treatment of17oc-acetoxy-llot-hydroxy-progesterone with methanesulfonyl chloride,according to the procedure of Example 10.

EXAMPLE 18 l7a-acetoxy5,20-dioxo-1lwrnesoxy-A-nor 3,5 secopregnan-3-oicacid is prepared by ozonolysis of l7a-acetoxy-llu-mesoxy-progesterone,according to the procedure of Example 11.

EXAMPLE 19 17vt-acetoxy-desA-pregn-9-ene-5,20-dione is prepared froml7u-acetoxy-5,20-dioxo-1la-mesoxy-A-nor-3,5-secopregnan-S-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the pro cedure of Example 12.

EXAMPLE 20 l7a-acetoxy-20B-hydroxy-desA-pregn-4-en-S-one is preparedfrom 17 a-acetoxy-desA-pregn-9-en-5,20 dione by reduction andreoxidation according to the procedure of Example 13.

EXAMPLE 21 17a acetoxy-2OB-hydroxy-9B,lOB-desA-pregnan-S-one is preparedfrom 17a-acetoxy-20fi-hydroxy-desA-pregn-9- en-5-one by hydrogenationunder acidic conditions in the presence of a rhodium catalyst, accordingto the procedure of Example 15.

EXAMPLE 22 l7a-acetoxy 20,8 hydroxy-9B,lOwpregn-4-en-3-one is preparedby condensing methyl vinyl ketone with 170:-acetoxy-2OB-hdroxy-9B,lOfi-desA-pregnan 5 one according to the procedureof Example 5 except instead of conducting the condensation in absoluteethanol and catalyzing it with sodium ethoxide, the condensation isconducted in acetic acid and is catalyzed with p-toluene sulfonic acid.

EXAMPLE 23 20fi-hydroxy-4-methyl-9fi,l0a-pregn-4-en-3-one is prepared bycondensing 20fi-hydroxy-9fi,lOfl-desA-pregnan- 5-one and ethyl vinylketone according to the procedure of Example 5.

EXAMPLE 24 17fi-hydroxy-5-oxo-3,5-seco-A-nor-androstan-3-0ic acid isprepared by ozonolysis of testosterone according to the procedure ofExample 1.

EXAMPLE 25 17B- hydroxy-lOa-desA-androStan-S-One and175-hydroxy-l0l8-desA androstan-S-one are prepared from 175-hydroxy-5-oxo-3,S-seco-A-norandrostan 3 oic acid by conversion of thelatter to its sodium salt followed by pyrolysis, according to theprocedure of Example 2.

EXAMPLE 26 l7B-hydroxy-desA-androst-9-en-5-one is prepared from1713-hydroxy-l()u-desA-androstan-S-one by bromination followed bydehydrobromination, according to the procedure of Example 3.

EXAMPLE 26a DesA-androst-9-ene-5,l7-dione is prepared from 17,6-hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2percent chromic acid solution in percent acetic acid. The so-obtaineddesA-androst-9-ene-5,l7- dione is recrystallized from cyclohexane andmelts at 123-1235; [a] 1=+83 (c.=0.l02l, dioxane).

EXAMPLE 27 A solution of 236 mg. of l7,8 hydroxy-desA-androst-9-en-5-one in 40 ml. percent ethanol and 5.25 ml. 2 N aqueous sodiumhydroxide solution was hydrogenated with one mole equivalent of hydrogenover 236 mg. of prereduced 5 percent rhodium on alumina catalyst. Afterseparation of catalyst, the solution was concentrated in vacuo todryness, and the residue taken up in one liter of ether. The ethersolution was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness in vacuo. From the residue 17;.8-hydroxy-913,l0,8-desA-androstan-S-one was obtained by crystallization. M.P. 144.5-145";[a] -22 (c.=0.103; dioxane). The flit-acetate (i.e.17fi-acetoxy-9fi,IOB-desA-androstan-S- one) is obtained by acetylationof testosterone followed by ozonolysis, pyrolysis, bromination anddehydrobromination, and reduction according to the methods of Examples24, 25, 26 and 27 respectively, and melts at 118-119; [a] 28 (c.=0.l03;dioxane).

EXAMPLE 28 A solution of 238 mg. of 17B-hydroxy-9;3,10B-desA-androstan-S-one, 1 m1. of ethylene glycol and catalytic amount ofp-toluene sulfonic acid in ml. of anhydrous benzene was slowly distilleduntil no more water was coming over. The solution was then concentratedin vacuo to a small volume, and17fl-hydroxy-9y8,lOfi-desA-androstan-5-one S-ethylene ketal was obtainedfrom the residue by crystallization. M.P. -1l6; [a] 9 (0.: 0.0987;dioxane).

EXAMPLE 29 To a solution of 282 mg. of 17 3-hydroxy-9fi,l0l3-desA-androstan-S-one S-ethylene ketal in 50 ml. of methylene chloride wasadded 1 equivalent of 2 percent chromic acid in pyridine, and thereaction mixture then stirred overnight. The reaction mixture was thenwashed with 10 percent aqueous sodium hydrogen sulfite, 2 N aqueoussodium carbonate, water, then dried over anhydrous sodium sulfate andconcentrated in vacuo to dryness. Crystallization of the residue gave918,10B-desA-androstane-5,17-dione S-monoethylene ketal. Splitting ofthe ketal in acetone solution in the presence of a catalytic amount ofp-toluene sulfonic acid gives 95,10B-desA- androstane-5,l7-dione whichmelts, after recrystallization from cyclohexane, at 775-78"; [a] +55(c.=0.l07; dioxane).

29 EXAMPLE 30 To a preformed solution of one mole equivalent ofprop-1'-inyl lithium in 100 ml. of anhydrous liquid ammonia was addedtetrahydrofuran solution of 200 mg. of 9 8,105 desA androstane5,17-dione S-mono-ethylene ketal, and the reaction mixture stirred fortwo hours. After addition of one gram of ammonium chloride, cooling wasdiscontinued, and the reaction mixture allowed to evaporate. The residuewas extracted with methylene chloride, the extract was washed withwater, dried over anhydrous sodium sulfate and evaporated. The residuewas dissolved in 20 ml. of acetone and the catalytic amount ofp-toluenesulfonic acid added, and the solution was refluxed for twohours, then poured in water and extracted in methylene chloride. Themethylene chloride extract was washed with water, then dried overanhydrous sodium sulfate and evaporated to dryness in vacuo.Crystallization of the residue gave 17u-(prop-1'-inyl)-17B-hydroxy-9B,1OB-desA-androstan-S-one.

EXAMPLE 31 17a (prop-1'-inyl 17,8 hydroxy-9,3,10a-androstan-4- en-3-oneis prepared by condensing methyl vinyl ketone with 170: (prop-1 inyl)17B hydroxy-95,10fi-desA- androstan-S-one according to the procedure ofExample 5. The product melts at 164-165 EXAMPLE 32 To a stirred solutionof one mole equivalent of 2- methyl-prop-Z-enyl magnesium bromide in 100ml. of ether at room temperature was added dropwise a solution of 280mg. of 9,8,lOfl-desA-androstane-S,l7-dione mono-ethylene ketal in 100ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour.After cooling in an ice-salt bath, a saturated solution of sodiumsulfate was slowly added to decompose the Grignard complex. This wasfollowed by addition of anhydrous sodium sulfate. The solution wasseparated by filtration and concentrated in vacuo to dryness. Thesolution of the residue and of a catalytic amount of p-toluene sulfonicacid in 20 ml. of acetone was refluxed for two hours, then poured inwater and extracted in methylene chloride. Methylene chloride extractwas washed with water, dried over anhydrous sodium sulfate andevaporated to dryness. From the residue 17a (2'methyl-prop-2'-enyl)-17/3-hydroxy- 9,3,lOfl-desA-androstan-S-one wasobtained.

EXAMPLE 33 17a (2'methyl-prop-2'-enyl)-17,B-hydroxy-9B,10aandrost-4-en-3-one is preparedfrom 17a-(2-methyl-prop- 2' enyl) 17,3hydroxy-95,IOB-desA-androstan-S-one by condensation of the latter withmethyl vinyl ketone according to the procedure of Example 5. The productmelts at l06108.

EXAMPLE 34 16a acetoxy 2O ethylenedioxy-pregn-4-en-3-one is prepared byacetylation of 16u-hydroxy-20-ethylenedi0xy-pregn-4-ene-3,ZO-dione withone equivalent of acetic anhydride in pyridine solution at roomtemperature for 2 hours, followed by concentration to dryness in vacuo.16oz acetoxy 20 ethylenedi0Xy-5-oxo-3,5-seco- A-norpregnan-3-oic acid isprepared by ozonolysis of 16aacetoxy-ZO-ethylenedioxy-pregn-4-en-3-oneaccording to the procedure of Example 1.

EXAMPLE 35 16a acetoxy-20-ethylenedioxy-10a-desA-pregnan-5-one and 16aacetoxy-ZO-ethylenedioxy-IOfl-desA-pregnan-S- one are prepared from16a-acetoxy-ZO-ethylenedioxy-S- oxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis(according to the procedure of Example 2) and reacetylation with aceticanhydride and pyridine.

30 EXAMPLE 36 acetoxy 20 ethylenedioxy-desA-pregn-9-en-5- one isprepared from 16a-acetoxy-ZO-ethylenedioxy-10adesA-pregnan-S-one bybromination followed by dehydrobromination, according to the procedureof Example 3.

EXAMPLE 37 160: acetoxy 20-ethylenedioxy-9;3,IOB-desA-pregnan- 5-one isprepared from 16a-acetoxy-20-ethylenedioxydesA-pregn-9-en-5-one bhydrogenation under basic conditions in the pressure of a rhodiumcataylst, according to the procedure of Example 14.

EXAMPLE 38 16a hydroxy 20-ethylenedioxy-9/3,10a-pregn-4-en-3- one isprepared by condensingl6a-acetoxy-20-ethylenedioxy-desA-9B,1()fi-pregnan-S-one with methylvinyl ketone according to the procedure of Example 5.

EXAMPLE 39 EXAMPLE 40 16a methyl 20 ethylenedioxy 10oz desA pregnan- 5one and 16a methyl 20 ethylenedioxy 10B desA- pregnan 5 one are preparedfrom 1601 methyl 20 ethylenedioxy 5 oxo 3,5 seco A norpregnan 3 oic acidby conversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 41 1604 methyl 20 ethylenedioxy desA pregn 9 en 5 one isprepared from 16a methyl 20 ethylenedioxy 10a desA pregnan 5 one bybromination followed by dehydrobromination, according to the procedureof Example 3.

EXAMPLE 42 16a methyl 20 ethylenedioxy 95,105 desA- pregnan 5 one isprepared from 160: methyl 20 ethylenedioxy desA pregn 9 en .5 one byhydrogenation under basic conditions in the presence of a rhodiumcatalyst, according to the procedeure of Example 14.

EXAMPLE 43 16a methyl 20 ethylenedioxy 95,100: pregn 4 en 3 one isprepared by condensing 16a methyl 20 ethylenedioxy 9,8,105 desA pregnan5 one with methyl vinyle ketone, according to the procedure of Examlpe5.

EXAMPLE 44 21 acetoxy 11a hydroxy 20 ethylenedioxypregn 4 en 3 one isprepared by microbiological treatment of21-acetoxy-20-ethylenedioxy-pregn-4-en-3- one, according to theprocedure of Example 17. 21- acetoxy 11oz mesoxy 20 ethylenedioxy pregn4 en 3 one is prepared by treatment of 21 acetoxy- 11a, hydroxy 20ethylenedioxy pregn 4 ene 3 one with methanesulfonyl chloride, accordingto the procedure of Example 10.

EXAMPLE 45 21 acetoxy 11a mesoxy 2O ethylenedioxy 5-oxo-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of21-acetoxy11a-mesoxy-20-ethylenedioxy-pregn- 4-en-3-one, according tothe procedure of Example 11.

EXAMPLE 46 21 acetoxy 20 ethylenedioxy desA pregn 9 en one is preparedfrom 21 acetoxy 20 ethylenedioxy 11oz mesoxy 3,5 seco A norpregnan 3 oicacid by conversion of the latter to its sodium salt followed bypyrolysis, according to the procedure of Example 12, except that thecrude product is reacetylated by treatment with acetic anhydride/pyridine prior to its being worked-up.

EXAMPLE 47 21 acetoxy 20 ethylenedioxy 95,105 desA- pregnan 5 one isprepared from 21 acetoxy 20 ethylenedioxy desA pregn 9 en 5 one byhydrogenation under acidic conditions in the presence of a rhodiumcatalyst, according to the procedure of Example 15.

EXAMPLE 48 21 hydroxy 20 ethylenedioxy 95,108 pregn 4 en 3 one isprepared from 21 acetoxy 20 ethylenedioxy 85,10 8 desA pregnan 5 one bycondensing the latter with methyl vinyl ketone, according to theprocedure of Example 22.

EXAMPLE 49 11a mesoxy 16u,17a isopropylidenedioxy progesterone isprepared by treatment of110L-hydl'OXy-160C,17uisopropylidenedioxy-progesterone with methanesulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 50 5,20 dioxo 11m mesoxy 160:,171 isopropylidenedioxy 3,5 seco Anorpregnan 3 oic acid is prepared by ozonolysis of 11a mesoxy 16 x,17uisopropylidenedioxy progesterone, according to the procedure of Example11.

EXAMPLE 51 16a,17a isopropylidenedioxy desA pregn 9 en 5,20 dione isprepared from 5,20 dioxo 11a mesoxyl6ot,l7a isopropylidenedioxy 3,5 secoA norpregnan-3-oic acid by conversion of the latter to its sodium salt,followed by pyrolysis according to the procedure of Example 12.

EXAMPLE 52 205 hydroxy 16a,17oz isopropylidenedioxy desA- pregn 9 en 5one is prepared from 160:,l7a-iSO- propylidenedioxy desA pregn 9 ene5,20 dione by reduction and reoxidation, according to the procedure ofExample 13.

EXAMPLE 53 20;? hydroxy 16u,17u isopropylidenedioxy 95,10,8- desApregnan 5 one is prepared from 206 hydroxy- 160:,17ozisopropylidenedioxy desA pregn 9 en 5 one by hydrogenation according tothe procedure of Example 14.

EXAMPLE 54 2018 hydroxy l6oc,17ot isopropylidenedioxy 918,10- pregn 4 en3 one is prepared by condensing methyl vinyl ketone with 205 hydroxy16:1,17u isopropylidenedioxy desA 913,105 pregnan 5 one according to theprocedure of Example 5.

EXAMPLE 55 7ot,17u dimethyl 1718 hydroxy 5 oxo 3,5 seco- A-norandrostan3 oic acid is prepared from 711,170:- dimethyl-testosterone byozonolysis of the latter, according to the procedure of Example 1.

EXAMPLE 56 70:,171 dimethyl 17B hydroxy oz desA androstan-S-one and 7a,17a dimethyl-17fi-hydroxy-1713-desA- androstan-S-one are prepared from7a,17a-dimethyl-l7;8- hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acidby conversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 57 741,171 dimethyl 176 hydroxy desA androst- 9-en-5-one isprepared from 7a,17u-dimethyl17;3-hydroxy-IOa-desA-andrOstan-S-One bybromination followed by dehydrobrornination, according to the procedureof Example 3.

EXAMPLE 58 ,l7u. dirnethyl 17s hydroxy desA 9 8,105 androstan-S-one isprepared from 7a,l7ot-dimethyl-l75-hydroxy-desA-androst-9-en-5-one byhydrogenation in the presence of a rhodium catalyst, according to theprocedure of Example 4.

EXAMPLE 59 7m,17a-dirnethyl-9,B,lOct-testosterone is prepared from7a,17cx dimethyl 17,6 hydroxy desA 95,10fi androstan-S-one by condensingthe latter with methyl vinyl ketone, according to the procedure ofExample 5.

EXAMPLE 6O 1la-mesoxy-17a-methyl-progesterone is prepared from11u-hydroxy-lZa-methyl-progesterone by treatment of the latter withmethane sulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 61 11a mesoxy 17oz. methyl 5,20 dioxo 3,5 seco-A-norpregnan-B-oic acid is prepared fromllu-mesoxyl7a-methyl-progesterone by ozonolysis of the latter, accordingto the procedure of Example 11.

EXAMPLE 62 l7u-methyl-desA-pregn-9 ene,5,20 dione is prepared from11a-mesoxy-17a-methyI-S,ZO-dioxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12.

EXAMPLE 63 20B-hydroxy-17mmethyl-desA-pregn-9-en-5-one is prepared from17ot-Inethyl-desA-pregn-9-en-5,20-dione according to the procedure ofExample 13.

EXAMPLE =64 2'0fi-hydroxy-17a-methyl-9-B,IOB-desA-pregnanJ-one isprepared from 17ot-methyi-2()fl-hydroxy-desA-pregnan-9- ene-S-oneaccording to the procedure of Example 15.

EXAMPLE 65 20/3 hydroxy 17o: methyl-93,10a-pregn-4-en-3-one is preparedby condensing 17ot-methyl-20B-hydroxy-9fl,105- desA-pregnan-S-one withmethyl vinyl ketone, according to the procedure of Example 4.

EXAMPLE 66 A solution of 12.8 g. of lia-methyltestosterone in 200 ml. ofmethylene chloride and ml. of ethyl acetate was ozonized for 1 hour and5 mintues at 70 (acetone- Dry Ice bath) until a blue color developed.After oxygen was bubbled through, the solution was then concentrated atroom temperature in vacuo. The residue was dissolved in 400 m1. ofacetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, thesolution was left overnight at 0. It was then evaporated to dryness invacuo, the residue taken up in ether, and the ether solution extractedwith 2 N aqueous sodium carbonate (12x50 ml.). The combined carbonateextracts were cooled in ice, and acidified with concentratedhydrochloric acid. The aqueous suspension of precipitated organic acidwas extracted With methylene chloride, this extract was washed withwater, dried over anhydrous sodium sulfate and evap- 33 orated giving asa colorless crystalline material 175- hydroxy 17a. methyl oxo 3,5 seco Anorandrostan-3-oic acid. After recrystallization from acetonehexane, itmelted at 195197, [a] =9.8 (c.=1.0 in chloroform).

EXAMPLE 67 A solution of g. of 17/8-hydroxy-17a-methyl-5-oxo-3,5-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was madealkaline to phenolphthalein with sodium ethoxide, and evaporated todryness. The residual powdery sodium salt was mixed well with 32 g. ofsodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), andthe mixture heated at 290 in vacuo for 4 hours. After cooling to roomtemperature, a large excess of water was added, and the resultantsuspension extracted with 2 liters of ether. The ether extract waswashed with water, aqueous 2 N sodium carbonate solution, and again withwater, dried and evaporated. This gave a sirupy residue, which by thinlayer chromatograms and infrared spectra consisted of 178-hydroxy-17a-methyl- IOwdesA-androstan-S-one as the major and17,8-hydroxy- 17a-methyl-10,8-desA-androstan-5-one as the minor product.

Three additional pyrolyses were performed as described above, and thecombined products so-obtained was chromatographed on a 850 g. silica gelcolumn, using 5% ethylacetate in benzene as the eluent. Thischromatography yielded17/3-hydroxy-17a-methyl-10ot-desA-androstan-5-one, which afterrecrystallization from petroleum ether melted at 96-97", [0c] =Z8.2(c.:0.5 in chloroform).

Further eluates of the column gave product, 178-hydroxy-lh-methyl-IOfl-desA-androstan-S-one which, when recrystallizedfrom ether, melted at 165-167",

(c.=0.5 in chloroform).

To a soltuion of 2.2 g. of the mixture of 17fi-hydroxy-17u-methyl-10a-desA-androstan-5-one and 17B-hydroxy-17a-methyl-10B-desA-androstan-5-one (obtained by the above pyrolysisprocedure) in 50 ml. of absolute ethanol were added 20.1 ml. of asolution prepared by dissolving 2.48 g. of sodium methyl in 250 ml. ofabsolute ethanol. The reaction mixture was stirred overnight at roomtemperature. It was then acidfied with 2 ml. of glacial acetic acid, andevaporated to dryness. The residue was extracted in ether (1 liter) andthe ether extract washed with water, dried, and evaporated. The residuewas crystallized from petroleum ether giving a quantitative yield of17B-hydroxy-Not-methyl-10ot-desA-androstan-5-one.

EXAMPLE 68 To a solution of 11.2 g. of 17/3-hydroxy-17a-methyl-10a-desA-androstan-5-one in 1260 ml. of anhydrous ether, stirred andcooled in an ice-salt bath, were added first several drops of 30%hydrogen bromide in acetic acid, then dropwise a solution of 7.16 g. ofbromine in 20 ml. of glacial acetic acid. The rate of addition of thebromine solution was synchronized with the rate of disappearance ofexcess bromine. After bromination was complete, 53 ml. of 10% sodiumhydrogen sulfite solution and 53 ml. of aqueous 2 N sodium carbonatesolution were added to the reaction mixture while stirring. The etherlayer was then separated, washed with water, dried, and evaporated todryness in vacuo. The residue was dissolved in 250 ml. ofdimethylformamide, and heated with 7.5 g. of lithium carbonate at 100for 45 minutes. After cooling, 2 liters of ether were added and theether solution washed with water, 1 N hydrochloric acid, and then againwith water, dried and evaporated. The residue was dissolved in 200 ml.of glacial acetic acid, 12.6 g. of sodium acetate and 12.6 g. of zincpowder were added and the mixture heated for ten minutes at 80. Aftercooling to room temperature, the reaction mixture was filtered, andevaporated. The residue was dissolved in ethylacetate, and

washed with saturated sodium bicarbonate solution, then with water,dried and evaporated. The so-obtained residue was chromatographed on asilica gel column using 10% ethylacetate in benzene as the eluent whichgave first 175 hydroxy-17a-methyl-10u-desA-androstan-5-one, followed by17 3-hydroxy-17a-methyl-desA-androst-9-en-5- one. Afterrecrystallization from ether, the latter compound melted at 103-104",[a] =63.2 (c.=0.5 in chloroform).

EXAMPLE 69 A suspension of 1.25 g. of 5% rhodium on alumina catalyst ina mixture of 130 ml. of 95% ethanol and 26 ml. of 2 N sodium hydroxidewas prereduced. To this was then added a solution of 1.25 g. of 175hydroxy-17amethyl-desA-androst-9-en-5-one in ml. of ethanol, and thenthe mixture was hydrogenated at atmospheric pressure and roomtemperature. After one mole equivalent of hydrogen was absorbed, thereaction was stopped, the catalyst was removed by filtration, and thefiltrate evaporated in vacuo. To the residue 5 ml. of glacial aceticacid was added, the so-formed mixture then dissolved in 2 liters ofether, and the resultant cloudy solution was washed with water, thendried and evaporated. The residue was dissolved in 50 ml. of methylenechloride and oxidized with 5 ml. of 2% chromic acid in 90% acetic aciduntil green color of reaction mixture. After then being washed withsodium hydrogen sulfite solution 2 N sodium carbonate solution andwater, the reaction mixture was dried over sodium sulfate andevaporated. The residue was chromatographed very slowly on a 50 g.silica gel column, with 5% ethylacetate in benzene, and followed withthin layer chromatography. First,17,3-hydroxy-17a-methyl-9a,10adesA-androstan-S-one was eluted. After aminor amount of mixed material, 17,8-hydroxy-17a-methyl-9i3,10fl-desA-androstan-S-one was eluted. After recrystallization from ether-petroleumether, it melted at 9496.

EXAMPLE 70 17ot-methy1-9B,wot-testosterone is prepared from17amethyl-17fi-hydroxy-desA-9fi,IOB-androstan 5 one by condensation ofthe latter with methyl vinyl ketone, according to the procedure ofExample 5. The product melts at 128-129".

EXAMPLE 71 A solution of 6 g. of 1104,20,8-diacetoxy-pregn-4-en-3- onein ml. methylene chloride and 50 m1. of ethylacetate was ozonized at 70.After methylene chloride was removed by distillation in vacuo, theresidual solution was diluted to 100 ml. with ethylacetate. To this 5ml. of 30 percent hydrogen peroxide was added and left overnight at roomtemperature. The reaction mixture was concentrated to dryness in vacuo,the residue taken up in 1 liter of ether, and the resulting solutionextracted 10 times with 50 ml. portions of 2 N aqueous sodium carbonate.The carbonate extract was then acidified with ice-cold concentratedhydrochloric acid. The precipitated product was separated by filtration,and crystallized to give 11u,20,8-diacetoxy-5-oxo-3,S-seco A norpregnan-3-oic acid.

EXAMPLE 72 A methanolic solution of 5 g. of 11a,20fi-diacetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid was treated with one half-moleequivalent of sodium carbonate, and evaporated to dryness in vacuo.Potassium acetate (5 g.) was added to the residue which was thenpyrolyzed at 295 and 0.02 mm. The sublimate was chromatographed on asilica-gel column to give 11a,20,8 diacetoxy-lOB-desA- pregnan-S-one.

EXAMPLE 73 Bromination and dehydrobromination starting with11a,20fi-diacetoxy-IOB-desA-pregnan-S-one according to the procedure ofExample 3, gave 1lu,20p-diacetoxy-desA- pregn-9-en-5-one.

EXAMPLE 74 Hydrogenation of 1111,205-diacetoxy-desA-pregn-9 en- S-one inethanolic hydrochloric acid over percent rhodium on alumina catalyst atroom temperature and atmospheric pressure according to the procedure ofExample gave 11a,20B-diacetoxy-9fi,1OB-desA-pregnan-5-one.

EXAMPLE 75 1la,20b-diacetoxy-9fi,lO S-desA-pregnan-S-one was hydrolyzedin methanol solution with one mole equivalent of potassium carbonate togive 11a,20,8-dihydroxy-9fi,10B- desA-pregnan-S-one.

EXAMPLE 76 Condensation ofl10:,20fl-dlh3ldIOXY-9fi,lU'fi-(lflSA-Pffignan-S-one with methyl vinylketone according to the procedure of Example 5 gave 110:,203 hydroxy95,100:- pregn-4-en-3-one.

EXAMPLE 77 A solution of 3 g. of 17:x-ethyl-17/i-hydroxy-androsta-1,4-dien-3-one in 75 ml. of methylene chloride and ml. of ethyl acetatewas ozonized at -70 till it became blue. After evaporation to dryness,the residue was dissolved in 100 ml. of glacial acetic acid containing 5ml. of percent hydrogen peroxide, and set at room temperature for 2days. The reaction mixture was concentrated to dryness and the residuedissolved in one liter of ether. The ether solution was then extracted10 times with 25 ml. portions of aqueous 2 N sodium carbonate solution,and the carbonate extracts were acidified with ice-cold concentratedhydrochloric acid. The non-crystalline precipitate containing17a-ethyl-l'ifl-hydroxy-ltla-carboxy-desA- androstan-S-one wasseparatediby filtration and dried, then dissolved in 135 ml. of absoluteethanol, and after addition of 9 ml. of aqueous 2 N sodium hydroxide,boiled for 1 hr. The reaction mixture was concentrated in vacuo to asmall volume, and diluted with 1750 ml. of ether. The ether solution wasWashed with water, dried over anhydrous sodium sulfate, and concentratedin vacuo to dryness. The residue was crystallized from ether-petroleumether, to give 17a-ethyl-17B-hydroxy-10a-desA-androstan- 5-one, M.P.8990.

EXAMPLE 78 3-(17fi-hydroxy-5-oxo-3,5 seco A nor androstanl7a-yl-3-oicacid)-propionic acid lactone is prepared by ozonolysis of3-(3-oxo-17B-hydroxy-androst-4-en-17m-y1)- propionic acid lactone,according to the procedure of Example 1.

EXAMPLE 79 3 (17B hydroxy-S-oxo-lGa-desA-androstan-17a-yl)- propionicacid lactone and 3-(17,8-hydroxy-5-oxo-l05-desA-androstan-lh-yl)-propionic acid lactone are prepared from3-(17fi-hydroxy-5'oxo-3,5-seco A nor androstan-l7a-yl-3-oicacid)-propionic acid lactone by conversion of the latter to its sodiumsalt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 80 3-(17B-hydroxy 5 oxo desA androst-9-en-17u-yl)- propionicacid lactone is prepared from 3-(17fl-hydroxy-S-oxo-l0u-desA-androstan-17a-yl)-propionic acid lactone by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 81 3-(17B-hydroxy 5 oxo 9,9,1op'desA-androstan-lhyl)-propionicacid lactone is prepared from 3-(17,6-hydroxy-S-oxo-desA-anrost 9 en170a yl)-propionic acid lactone by hydrogenation in the presence of arhodium catalyst, according to the procedure of Example 4.

36 EXAMPLE s2 3 (175 hydroxy 3 oxo 95,10a androst 4 en-17m-yl)-propionic acid lactone is prepared by condensing 3 (175 hydroxy5 oxo 9 8,105 desA androstan- 17m-yl)-propionic acid lactone with methylvinyl ketone, according to the procedure of Example 5.

EXAMPLE 83 17a,20;20,21 bis methylenedioxy 11a mesyloxypreg-4en-3-one isprepared by treatment of l7oc,20;20,21 bismethylenedioxy-l 1ahydroxy-pregn 4-en-3-one with methanesulfonyl chloride according to theprocedure of Example 10.

EXAMPLE 84 170:,2O;20,21 bis methylenedioxy 11a mesyloxy-5-oxo-3,5seco-A-norpregnan 3 oic acid is prepared by ozonolysis of17a,20;20,21-biS-methylenedioxy-llwmesyloxy-pregn-4-en-3-one accordingto the procedure of Ex ample 11.

EXAMPLE 8S 17,20;20,21 bis methylenedioxy desA pregn 9- en-S-one isprepared from l7a,20;20,21 bis-methylenedioxy-l1a-mesyloxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid by conversion ofthe latter to its sodium salt followed by pyrolysis, according to theprocedure of Example 12.

EXAMPLE 86 17a,20;20,21 bis methylenedioxy 95,10 8 desA- pregnan-S-oneis prepared from 17a,20;20,2l-bis-methyl enedioxy-desA-pregn-9-en-5-oneby hydrogenation in the presence of a rhodium catalyst according to theprocedure of Example 14.

EXAMPLE 87 17a,20;20,21 bis methylenedioxy 913,100; pregn 4- en-3-one isprepared by condensing methylvinyl ketone with17a,20;20,21-bis-methylenedioxy-9fl,IOB-desA pregnan-S-one, according tothe procedure of Example 5.

EXAMPLE 88 20,8 hydroxy 9fl,10a pregna 1,4 dien 3 one was prepared bycondensation of 20,8 -hydroxy 95,1018- desA-pregnan-S-one with 1equivalent of methyl ethinyl ketone in boiling benzene solution,catalyzed by sodium hydride.

EXAMPLE 89 One ml. of Jones Reagent (0.004 mole CrO is added to 200 mg.of 17fi-hydroxy-9B,IOB-desA-androstan-Sone in 20 ml. of acetone at l0.The mixture is then left for 15 minutes at room temperature, and 5 ml.of ethanol then added. The resulting suspension is evaporated to drynessin vacuo, water is added to the residue and the undissolved moiety takenup in ether. The ether phase is then washed with a solution of sodiumbicarbonate and then with water, dried over sodium sulfate ad evaporatedto dryness. There is so obtained an oil which crystallizes upon theaddition of a small portion of petroleum ether. The so-obtained crystalsof 95,1OS-desA-androstane-ifldione melt, after recrystallization fromcyclohexane, at 775-78"; [a] +55 (c.=0.107, dioxane); R.D. in dioxane(c.:0.107%): A in m ([a1-value in degrees); 550(+70); 400(-|-297);350(4-798); 320(+2968) max; 300(+467); 299(0); 290(1890).

EXAMPLE 90 A solution of 250 mg. of l7fi-hydroxy-9BJ0 8-desA-androstan-5-one dissolved in 2.5 ml. of pyridine and 2.5 ml. of aceticanhydride, is left at room temperature for 18 hours. The mixture is thenevaporated to dryness at 11 mm., the residue taken up in ether, and theether phase washed with 1 N hydrochloric acid, sodium bicarbonate andwater, and then dried over sodium sulfate. After filtration andevaporation of the ether, the residue is then treated with a smallquantity of petroleum ether yielding crystals of17/3-acetoxy-9B,10,3-desA-androstan-5- one which, upon recrystallizationfrom methanol, melt at 118-l19; [cc] :28 (c.=0.103%, dioxane); R.D. indioxane (c.:0.103%): x in mg ([aJ-value in degrees); 400 (30); 356 350313 (+449) max.; 307 (+374) min.; 305 (+380) max.; 300 (+224); 293 (0);280 (-652).

EXAMPLE 91 A solution of 250 mg. of17fl-acetoxy-9fl,IOfi-desA-androstan-S-one in 60 ml. of 95% methanolcontaining 144 mg. of potassium hydroxide is refluxed for 60 minutes.The resulting mixture is evaporated to dryness in vacuo, water added tothe residue and the suspension extracted with ether. The ether phase iswashed with water, dried over sodium sulfate, filtered off, the solventremoved and the crystalline residue then crystallized from a smallvolume of cyclohexane, yielding crystals of 17fi-hydroxy-9S,IOB-desA-androstan-S-one which upon being recrystallized fromethylacetate melt at 144.5145; [111 :-22 (c.=0.103, dioxane), R.D. indioxane (c. =0.103); x in my. ([a]-value in degrees); 400 (7); 390 (0);350 (+52); 313 (+571) max.; 307 (+492) min; 305 (+504) max.; 300 (+324);293 (0); 290 (202).

EXAMPLE 92 A solution of 10 g. of1lfi-formyloxy-androsta-l,4-diene-3,17-dione in 100 ml. of acetic acidwas ozonized at 0 until thin layer chromatography did not show anystarting material. The reaction mixture was then poured into 100 ml. ofwater and the mixture was then heated to 100 for 30 minutes. The mixturewas then concentrated in vacuo and treated with 50 ml. of saturatedsodium bicarbonate solution. The undissolved material was extracted with100 ml. of ether. The extract was chromatographed on silica gel usingmethylene chloride. The eluates were concentrated and gave, on additionof hexane, 1IB-formyloxy-l0g-desA-androstane-5,l7-dione, M.P.

ll7-117.5 (recrystallized from acetone-cyclohexane), [a] :93 (dioxane).

EXAMPLE 93 By hydrolysis of 1lfi-formyloxy-lOE-desA-androstane-5,17-dione in 2% methanolic potassium hydroxide there is obtainedllfi-hydroxy-105-desA-androstan 5,17 dione, which melts at 154; [a] +96(dioxane).

EXAMPLE 94 250 mg. of 1lfl-hydroxy-IOE-desA-androstane-SJ7-dione and 250mg. of p-toluene sulfonic acid monohydrate in ml. of benzene wererefluxed in a nitrogen atmosphere for 6 hours. The reaction mixture wasthen washed with an aqueous solution of sodium bicarbonate and then withwater, dried over sodium sulfate, filtered and evaporated to dryness.The residue was then chromatographed over silica gel (5 g.) indichloromethane. Triturating the residue obtained from the first 250ml.eluted yielded crystals of desA-androst-9-ene-5,17-dione, which uponrecrystallization from cyclohexane melted at 123-l23.5.

EXAMPLE 95 The compound, 11,8-formyloxy-5,17-dioxo-3,5 seco-A- norandrostan-3-oic acid is prepared from11,8-formyloxyandrost-4-ene-3,17-dione by ozonolysis according to theprocedure of Example 11. The so-obtained product melts at 220-22l; [a]+107 (dioxane).

EXAMPLE 96 3.7 g. of the sodium salt of 1lB-formyloxy-5,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid and 12 g. of sodium phenylacetateare fused together in vacuo (0.1 torr.). When the bath temperaturereaches 220 the molten mass begins to decompose. The bath is then heatedfurther (within minutes) to a temperature of 290. Once this temperaturehas been reached the mixture is left for another 10 minutes at theinitial pressure of 0.1 torr. The distilled material is thenchromatographed over 30 g. of aluminum oxide (activity grade 3). Elutionwith a total of 200 ml. of petroleum ether-benzene (2:1), followed byevaporation of the solvent and trituration of the residue in thepresence of petroleum ether, yields desA-androst-9- ene-5,17-dione whichupon recrystallization from cyclohexane melts at 123123.5 [a] =+83(c.=0.1021, dioxane).

EXAMPLE 97 20/3-acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid isprepared by ozonolysis of 20'B-acetoxy-pregn-4-en-3-one according to theprocedure of Example 1.

EXAMPLE 98 A solution of 15.15 g. of 20fi-acetoxy-5-oxo-3,S-seco-A-nor-pregnan-3-oic acid in 250 ml. of 75% methanol containing 10 g. ofpotassium hydroxide was refluxed for 2 hours. The methanol was thenremoved in vacuo and the residue was dissolved in ml. of water. Thesolutior. was chilled to 0 and acidified to congo red by the addition of20% hydrochloric acid. There was thus obtained 20;?-hydroxy-5-ox-3,S-seco-A-nor-pregnan 3 oic acid, M.P. 181182, [a]; =13(dioxane).

A solution of 4.7 g. of 2-0fi-hydroxy-5-oxo-3,S-seco-A-nor-pregnan-3-oic acid in 100 ml. of methanol was neutralized with 1 Nsodium methylate solution against phenophthaleine. The solution was thenevaporated and the residue, consisting of20B-hydroxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid sodium salt, wasrefluxed with 100 ml. of quinoline for 8 hours. The cooled mixture waspoured on a mixture of g. of ice and 100 ml. concentrated hydrochloricacid and extracted with ether. The ether extract was worked up and theoily residue was chomatographed on silica gel. Elution with methylenechloride gave 10a-desA-pregnane-5,20-dione, M.P. 126-127 (crystallizedfrom isopropyl ether), [a] -=8Z (dioxane). Elution with methylenechloride containing 1% acetone gave ZOfl-hydroxy-IOa-deSA-pregnan 5 one,M.P. 104- 104.5 (crystallized from ether-hexane), [a] -=-10 (dioxane).The fractions obtained with methylene chloride containing 540% acetonewere evaporated and the oily residue was dissolved in 40 ml. of acetone.The solution was treated with 3 ml. of Jones reagent (0.004 mole CrO at10 and kept at the same temperature for 10 minutes. After the additionof 5 ml. of methanol, the solution was evaporated and the residue wasdiluted with water and extracted with ether. The ether extract wasworked up and gave 10a-deSA-pregnane-5,20-dione.

EXAMPLE 99 20 8-hydroxy-desA-pregn-9-en-5-one is prepared from20fi-l1ydroxy-10a-desA-pregnan-5-one by bromination followed bydehydrobromination, according to the procedure of Example 3. Theso-obtained product, aftger recrystallization from methylenechloride-petroleum ether, melts at 122-123.

EXAMPLE 100 5,20-dioxo-3,S-seco-A-nor-pregnan-3-oic acid is prepared byozonolysis of progesterone according to the procedure of Example 1.

EXAMPLE 101 l0a-desA-pregna-5,20-dione and IOB-desA-pregnan 5, 20-dioneare prepared from 5,20-dioxo-3,5-seco-A-pregnan-3-oic acid by conversionof the latter to its sodium salt followed by pyrolysis, according to theprocedure of Example 2.

EXAMPLE 102 The compound, desA-pregn-9-ene-5,20-dione is prepared from10a-desA-pregna-5,20-dione by bromination followed by dehydrobrominationaccording to the procedure of Example 3. The so-obtained product, afterrecrystallization from ether, melts at Ill-113.

39 EXAMPLE 103 15 ml. of 0.8% potassium permaganate solution was addedto a mixture of 11 g. of ZOfiZ-tetrahydropyranyloxypregn-4-en-3-one, 500ml. of an azeotropic mixture of tertiary butanol and water, 7 g. ofpotassium carbonate, 20 ml. of water and 120ml. of 7% sodiummetaperiodiate solution with vigorous stirring at room temperature. 250ml. of 7% sodium metaperiodate and 20 ml. of 0.8% potassium permanganatesolution were then simultaneously added within 15 minutes. To theso-obtained suspension, 220 ml. of 7% sodium metaperiodate solution and,in order to keep the mixture violet in color, 15 ml. of 0.8% potassiumpermanganate solution were then added in the course of 30 minutes. Themixture was then stirred for 90 minutes, filtered over a filter aid(Hyflo) and the residue was washed with 100 ml. of tert. butanol-waterazeotrope. The filtrate was evaporated in vacuo at 50 and the residuediluted with 150 ml. of water. The solution was acidified with cold 20%hydrochloric acid to congo red, and the resultant oily material taken upin 150 ml. of methylene chloride. The organic extract was washed withwater, dried and evaporated and the residue was purified by filtrationover silica gel using methylene chloride and methylene chloridecontaining 12% ethanol as the elution agents. There was thus obtained20;8-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as aviscous oil.

EXAMPLE 104 To a solution of 35.8 g. of a mixture of 20aand20phydroxy-pregn-4-en-3-one in 500 ml. of anhydrous benzene, there wereadded 75 ml. of 1% p-toluenesulfonic acid in benzene and then 35 ml. ofdihydropyran. The reaction mixture was allowed to stand at roomtemperature for 16 hours, washed with 2% aqueous sodium bicarbonate andwater, dried and concentrated in vacuo at 11 mm. Hg and 80. The residueconsisting of 20mand 20fl-tetrahydropyranyloxy-pregn-4-en-3-one wasdissolved in 2 liters of tert. butanol-water azeotrope followed by theaddition of a solution of 33 g. of potassium car-z bonate in 80 ml. ofwater and 620 ml. of 7% aqueous sodium metaperiodate solution. To thereaction mixture there was first added with vigorous stirring at roomtemperature, 75 ml. of 0.8% potassium permanganate and thereaftersimultaneously within 30 minutes 1350 ml. of 7% sodium metaperiodatesolution and 100 ml. of 0.8% potassium permanganate solution. Another1080 ml. of 7% sodium metaperiodate solution and 100 ml. of 0.8%potassium permanganate solution were then added within 45 minutes. Thereaction mixture was then stirred for 1 hour, filtered over a filter aid(Hyfio) and the residue was washed with 250 ml. of tert. butanol-waterazeotrope. The filtrate was evaporated, the residue taken up in 800 ml.of water and filtered. The alkaline filtrate was chilled to acidifiedwith cold 20% hydrochloric acid and extracted with methylene chloride.After working up, the extract afforded a mixture of 20aandZOB-tetrahydropyranyloxy-S-oxo-3,5-seco-A-nor-pregnan-3-oic acid as aviscous oil. This oil was dissolved in 300 ml. of methanol andneutralized with 1 N lithium methylate. The solution was evaporated todryness in vacuo. The oily residue was dissolved in 300 ml. of benzene,evaporated again and dried at 11 mm. Hg and 100 for 2 hours. There wasobtained a mixture of the lithium salts of 20w and 20B-tetrahydropyranyloxy 5 0x0 3,5 seco A nor pres nan-3-oic acid as anamorphous powder.

EXAMPLE 105 A solution of 9 g. of 20;.8-tetrahydropyranyloxy-S-oxo-3,5-seco-A-nor-pregnan-3-oic acid in 100 ml. of methanol was neutralizedwith 1 N lithium methylate solution against phenolphthalein, followed byevaporation in vacuo to dryness. The so-obtained residue was taken up inbenzene, and the benzene evaporated yielding 20 8- tetrahydropyranyloxy5 oxo 3,5 seco A nor pregnan-3-oic acid lithium salt as asemi-crystalline powder.

5 g. of this lithium salt, 7.5 g. of anhydrous sodium acetate and 7.5 g.of anhydrous potassium acetate were mixed and pyrolyzed at 002-01 mm. Hgand 290 for 4 hours. The distillate was chromatographed on silica gelusing methylene chloride and methylene chloride containing 0.5l% acetoneas the elution agents. The fractions were evaporated and gave ontreatment with etherhexane 20B tetrahydopyranyloxy 10oz desA-pregnan-5-one, M.P. 125.5127 (crystallized from methanol) [u] :53 (dioxane).

The oily part of the evaporation residue containing besides the lattercompound the compound ZOE-tetrahydropyranyloxy-l0,3-desA-pregnan-5-oneethanol. After the addition of 10 ml. of water and 200 mg. ofp-toluenesulfonic acid monohydrate, the solution was refluxed for 60minutes and evaporated in vacuo. The residue was then treated with waterand extracted with ether. The ether extract was worked up and gaveZOB-hydrOXy-IOu-desA- pregnan-S-one, M.P. 104.5-105 (crystallized fromether-hexane) EXAMPLE 106 250 mg. ofZOB-tetrahydropyranyloxy-10u-desA-pregnan-S-one was dissolved in 8 ml.of ethanol and after the addition of 1 ml. of water and 15 mg. ofp-toluenesulfonic acid monohydrate refluxed for 1 hour. The reactionmixture was then evaporated and the residue taken up in ether. The etherextract was worked up and gave 20,6 hydroxy 10a desA pregnan 5 one, M.P.104.5405 (crystallized from ether-hexane).

EXAMPLE 107 10 g. of a mixture of 20aand205-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid lithiumsalt was mixed with 15 g. each of anhydrous sodium acetate and anhydrouspotassium acetate and pyrolyzed at 0.01 0.1 mm. Hg and 290 for 5 hours.The distillate was dissolved in 100 ml. of ethanol and, after theaddition of 15 ml. of water and 250 mg. of p-toluenesulfonic acidmonohydrate refluxed for 70 minutes. The reaction mixture was thenevaporated, the residue was treated with 50 ml. of 5% sodium bicarbonatesolution and extracted with ether. On working up, the extract gave anoily residue of 200:- and ZOB-hydroxy-10a-desA-pregnan-5-one, which wasdissolved in ml. of acetone, treated with 10 ml. of Jones reagent at l0and kept at 10 for 15 minutes. The suspension obtained was treated with15 ml. of ethanol, kept for 10 minutes at room temperature andevaporated. The residue was diluted with water and extracted with ether.The extract was worked up and gave, on addition of hexane,10u-desA-pregnane-5,20-dione, M.P. 126l27 (crystallized from isopropylether). The above pyrolysis was carried out in the same manner using 10g. of the lithium salt mixture and 30 g. of sodium phenylacetate.

EXAMPLE 108 40 ml. of 0.8% potassium permanganate solution was addedwith vigorous stirring to a mixture prepared from 25 g. of testosteroneacetate, 1000 ml. of tert. butanolwater azeotrope, 16.8 g. of potassiumcarbonate and 300 ml. of 7% aqueous sodium metaperiodate solution. Inthe course of 15 minutes, 660 ml. of 7% sodium metaperiodate solutionand 40 ml. of 0.8% potassium permanganate solution were thensimultaneously added to the so-formed reaction mixture, followed by theaddition of 540 ml. of 7% sodium metaperiodate solution and 20 ml. of0.8% potassium permanganate solution in the course of 30 minutes. Themixture was then stirred for minutes, filtered over a filter aid (Hyflo)and the residue was washed with ml. of tert. butanol-water azeotrope.The filtrate was worked up as described in Example 104 and gave17B-acetoxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid, a viscous oil.This oil was dissolved

